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University of Cape Town
1.
Sims, Danica Anne.
The role of T-box transcription factor TBX3 in rhabdomyosarcoma.
Degree: Image, Human Biology, 2016, University of Cape Town
URL: http://hdl.handle.net/11427/28264 
► Cancer remains one of the leading causes of death worldwide due to late diagnosis and ineffective treatment options. To address this problem requires the elucidation…
(more)
▼ Cancer remains one of the leading causes of death worldwide due to late diagnosis and ineffective treatment options. To address this problem requires the elucidation of the molecular mechanisms, including the signaling pathways and transcription factors that drive cancer initiation and progression. In this regard, our laboratory has been particularly interested in the embryonically important T - box family of transcription factors which has been heavily implicated in promoting initiation and progression of a long list of cancers. For example, the overexpression of the T - box factor TBX3, has been reported to function in promoting immortalization, migration, invasion and tumour formation in a number of epithelial - derived malignancies. Furthermore, our laboratory recently reported that TB X3 is also overexpressed in a wide range of sarcoma subtypes including rhabdomyosarcomas. This suggests that TBX3 may also contribute to the development and/or progression of sarcomas and potentially may serve as a biomarker for their diagnosis and targete d therapy. This is exciting because sarcomas are diverse and heterogeneous cancers with varying clinical behaviours, high rates of metastasis and recurrence and are notoriously resistant to current chemotherapies. However, whether TBX3 is a molecular drive r of these mesenchymal - derived cancers remains to be determined. This project therefore aimed to elucidate the role of TBX3 overexpression in embryonal rhabdomyosarcomas (ERMS) which is the most common soft tissue sarcoma in children and adolescents. To this end, ERMS
cell culture models were established in which TBX3 was either stably knocked down or stably overexpressed and the resulting cells were tested for several features of the cancer phenotype using in vitro and in vivo experiments. The results show that TBX3 promotes
cell proliferation, anchorage independent growth and
cell migration in vitro and tumour formation and invasion in vivo. This study also provides evidence that nucleolin binds to, and co - operates with, TBX3 to promote proliferation and migration of ERMS cells. Furthermore, data from initial experiments reveal that Hsc70 interacts with TBX3, to possibly increase its protein stability, and that oncogenic c - Myc and AKT 1 positively regulat e TBX3 levels in ERMS. This, albeit preliminary data, suggest that Hsc70, c - Myc and AKT1 are responsible, in part, for the overexpression of TBX3 in ERMS. Together findings from this study implicate TBX3 as an oncogene in ERMS and suggest that TBX3, nucleolin, Hsc70, c - Myc and AKT may be used in combination as biomarkers for the diagnosis and targeted therapy of ERMS.
Advisors/Committee Members: Prince, Sharon (advisor), Peres, Jade (advisor).
Subjects/Keywords: Medical Cell Biology
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APA (6th Edition):
Sims, D. A. (2016). The role of T-box transcription factor TBX3 in rhabdomyosarcoma. (Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/28264
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Sims, Danica Anne. “The role of T-box transcription factor TBX3 in rhabdomyosarcoma.” 2016. Thesis, University of Cape Town. Accessed February 28, 2021.
http://hdl.handle.net/11427/28264.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Sims, Danica Anne. “The role of T-box transcription factor TBX3 in rhabdomyosarcoma.” 2016. Web. 28 Feb 2021.
Vancouver:
Sims DA. The role of T-box transcription factor TBX3 in rhabdomyosarcoma. [Internet] [Thesis]. University of Cape Town; 2016. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11427/28264.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Sims DA. The role of T-box transcription factor TBX3 in rhabdomyosarcoma. [Thesis]. University of Cape Town; 2016. Available from: http://hdl.handle.net/11427/28264
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Vermont
2.
Director, Laura Taylor.
A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins.
Degree: MS, Cellular, Molecular and Biomedical Sciences, 2014, University of Vermont
URL: https://scholarworks.uvm.edu/graddis/264
► A-kinase anchoring proteins (AKAPs) are signaling scaffolds which provide spatial and temporal organization of signaling pathways in discrete subcellular compartments. Through tethering the cyclic-AMP…
(more)
▼ A-kinase anchoring proteins (AKAPs) are signaling scaffolds which provide spatial and temporal organization of signaling pathways in discrete subcellular compartments. Through tethering the cyclic-AMP dependent protein kinase A (PKA), AKAPs target PKA activity to distinct regions in the
cell, bringing PKA in close proximity to its target proteins. This provides a high level of specificity and regulation of PKA and its role in mediating a number of biological processes, one of which is
cell migration.
Cell migration is a highly dynamic and fundamental process, when misregulated can lead to a number of pathologies. The process of
cell migration requires integration and coordination of actin cytoskeletal dynamics, adhesion turnover, and contractility. The important role of PKA in regulating the cellular processes involved in
cell migration has been extensively studied. Our lab has shown that PKA activity and spatial distribution through AKAPs are localized to the leading edge of migrating cells and are required for effective
cell migration, yet the specific AKAPs responsible remain unknown.
Traditional methods for identifying AKAPs suffer from a number of limitations. Therefore the objective of the enclosed work is to establish and characterize a novel approach for the identification of cytoskeletal and adhesion-associated AKAPs. We show for the first time, an in vitro approach to identify cytoskeletal AKAPs which may be responsible for localizing PKA to the leading edge of migrating cells.
Advisors/Committee Members: Alan K. Howe.
Subjects/Keywords: Medical Cell Biology; Molecular Biology
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APA (6th Edition):
Director, L. T. (2014). A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins. (Thesis). University of Vermont. Retrieved from https://scholarworks.uvm.edu/graddis/264
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Director, Laura Taylor. “A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins.” 2014. Thesis, University of Vermont. Accessed February 28, 2021.
https://scholarworks.uvm.edu/graddis/264.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Director, Laura Taylor. “A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins.” 2014. Web. 28 Feb 2021.
Vancouver:
Director LT. A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins. [Internet] [Thesis]. University of Vermont; 2014. [cited 2021 Feb 28].
Available from: https://scholarworks.uvm.edu/graddis/264.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Director LT. A Novel Approach For The Identification of Cytoskeletal and Adhesion A-Kinase Anchoring Proteins. [Thesis]. University of Vermont; 2014. Available from: https://scholarworks.uvm.edu/graddis/264
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
McMaster University
3.
Chew, Tracy.
THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE.
Degree: PhD, 2012, McMaster University
URL: http://hdl.handle.net/11375/12055
► The transcription factor interferon (IFN) regulatory factor 3 (IRF-3) plays a central role in the innate immune response to viral stimulation. IRF-3 participates in…
(more)
▼ The transcription factor interferon (IFN) regulatory factor 3 (IRF-3) plays a central role in the innate immune response to viral stimulation. IRF-3 participates in both the type I IFN-dependent and -independent signalling pathways that result in the induction of an antiviral state. The work presented in this thesis characterizes the central role of IRF-3 in the IFN-independent response to virus particle entry. In addition, novel splice variants of human IRF-3 are identified and characterized, implying a role for splice-mediated regulation of IRF-3-mediated antiviral signalling. Finally, a role for reactive oxygen species in the activation of IRF-3 following virus particle entry is described, with virus particle entry inducing danger associated molecular patterns associated with IRF-3 activation and IFN-independent antiviral gene expression. Taken together, this thesis characterizes the role of IRF-3 in the innate antiviral signalling pathways activated following viral stimulation, and highlight the importance of danger-associated molecular patterns as important mediators of antiviral signalling.
Doctor of Philosophy (PhD)
Advisors/Committee Members: Mossman, Karen L., Lichty, Brian D., Ashkar, Ali, Medical Sciences (Molecular Virology and Immunology Program).
Subjects/Keywords: innate immunity; virology; signalling; cell biology; molecular biology; cytokines; Medical Cell Biology; Medical Cell Biology
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APA (6th Edition):
Chew, T. (2012). THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/12055
Chicago Manual of Style (16th Edition):
Chew, Tracy. “THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE.” 2012. Doctoral Dissertation, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/12055.
MLA Handbook (7th Edition):
Chew, Tracy. “THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE.” 2012. Web. 28 Feb 2021.
Vancouver:
Chew T. THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE. [Internet] [Doctoral dissertation]. McMaster University; 2012. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/12055.
Council of Science Editors:
Chew T. THE ROLE OF INTERFERON REGULATORY FACTOR 3 IN THE INNATE ANTIVIRAL RESPONSE. [Doctoral Dissertation]. McMaster University; 2012. Available from: http://hdl.handle.net/11375/12055
McMaster University
4.
Korol, Anna.
Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells.
Degree: MSc, 2012, McMaster University
URL: http://hdl.handle.net/11375/12624
► Epithelial-mesenchymal transition (EMT) is a pathological process leading to the formation of anterior subcapsular cataract (ASC). Mediated by transforming growth factor beta (TGFβ), EMT…
(more)
▼ Epithelial-mesenchymal transition (EMT) is a pathological process leading to the formation of anterior subcapsular cataract (ASC). Mediated by transforming growth factor beta (TGFβ), EMT involves the transformation of the monolayer of lens epithelial cells (LECs) into spindle-shaped myofibroblasts, which manifest as plaques directly beneath the lens capsule. TGFβ-induced EMT leading to ASC has been associated with the upregulation of two specific matrix metalloproteinases (MMPs), MMP-2 and MMP-9. Having identified MMP-2 and MMP-9 as participants in the formation of cataracts, the specific roles of either of these MMPs have yet to be determined. The current study utilized MMP-2 and -9 knockout (KO) mice to determine their unique roles in TGFβ-induced EMT. First, adenoviral injection of active TGFβ1 into the anterior chamber of MMP-2 KO mice led to the formation of distinct αSMA-positive anterior subcapsular plaques, in contrast to treated MMP-9 KO eyes, which were resistant. Additionally, an ex vivo mouse LEC explant system was established in these KO lines. In the isolated lens epithelial explants, TGFβ triggered a transformation of LECs from a tightly packed cuboidal monolayer to an elongated mesenchymal phenotype. This process involved a disruption in epithelial cell contacts indicated by a loss of E-cadherin, and an acquisition of myofibroblast marker, αSMA. In the absence of MMP-2, TGFβ was still able to induce EMT with E-cadherin loss and concurrent αSMA expression. In contrast, LEC explants from MMP-9 KO mice treated with TGFβ did not acquire a characteristic spindle-like phenotype and showed substantially less αSMA expression. Results from both of these approaches were consistent; MMP-2, but not MMP-9, KO mice stimulated with TGFβ exhibited phenotypic changes typical of those described in ASC formation, namely a loss in cell attachments, multilayering of previously epithelial-like cells, and αSMA reactivity. Therefore, while MMP-2 is not necessary, MMP-9 is critical to TGFβ-induced EMT in LECs.
Master of Science (MSc)
Advisors/Committee Members: West-Mays, Judith, Medical Sciences.
Subjects/Keywords: EMT; cataract; lens; MMP; TGFβ; Medical Cell Biology; Medical Cell Biology
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APA (6th Edition):
Korol, A. (2012). Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/12624
Chicago Manual of Style (16th Edition):
Korol, Anna. “Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells.” 2012. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/12624.
MLA Handbook (7th Edition):
Korol, Anna. “Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells.” 2012. Web. 28 Feb 2021.
Vancouver:
Korol A. Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells. [Internet] [Masters thesis]. McMaster University; 2012. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/12624.
Council of Science Editors:
Korol A. Investigation into the Unique Roles of MMP-2 and MMP-9 in TGFβ-Induced Epithelial-Mesenchymal Transition in Lens Epithelial Cells. [Masters Thesis]. McMaster University; 2012. Available from: http://hdl.handle.net/11375/12624
University of Cambridge
5.
Roshan, Amit.
Stochasticity and order: studies of keratinocyte proliferation.
Degree: PhD, 2014, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/252966https://www.repository.cam.ac.uk/bitstream/1810/252966/3/license.txt
;
https://www.repository.cam.ac.uk/bitstream/1810/252966/4/Roshan_2014_PhD-37461.pdf.txt
;
https://www.repository.cam.ac.uk/bitstream/1810/252966/6/Roshan_2014_Agreement.pdf.txt
;
https://www.repository.cam.ac.uk/bitstream/1810/252966/5/Roshan_2014_PhD-37461.pdf.jpg
;
https://www.repository.cam.ac.uk/bitstream/1810/252966/7/Roshan_2014_Agreement.pdf.jpg
► A central tenet of stem cell biology has been that proliferating tissues are maintained through a cellular hierarchy comprising of self-renewing stem cells at the…
(more)
▼ A central tenet of stem cell biology has been that proliferating tissues are maintained through a cellular hierarchy comprising of self-renewing stem cells at the apex, multiple lineage-restricted short-lived progenitor cells, and post-mitotic differentiated cells. The wide range of colony sizes in cultured human keratinocytes has been taken to support this hypothesis. Contrary to this model, researchers using genetic lineage tracing in mouse epidermis have inferred a single progenitor population for homeostasis, and a quiescent stem cell population activated upon wounding or genetic mutation.
To study the proliferative behaviour of human keratinocytes, I used live imaging in vitro at single cell resolution. This shows two modes of proliferation: Type 1 cell division is stochastic with equal odds of generating dividing or non-dividing progeny, while Type 2 cell division predominantly produces two dividing daughters. These two modes are sufficient to explain the entire range of colony sizes seen after 7-12 days of culture and does not require a spectrum of proliferative ability.
This insight provides a simple way to study the effects of external factors on cell fate. To exemplify this, I observed the effects of epidermal growth factor (EGF) and the Wnt agonist R-spondin on proliferation. Here I find proliferation in type 2 colonies changes by changing the proportion of cells dividing. This has implications for the limited success of EGF therapies in clinical trials following burns.
To examine clonal contributions to wound repair, I used the mouse oesophageal epithelium which is exclusively composed of, and maintained by, a single progenitor population. I developed a micro-endoscopic wounding technique that produced localised superficial wounds. Here, I found that these wounds healed by uniform contribution from surrounding keratinocytes, demonstrating that reserve stem cells are not obligatory for wound repair.
In summary, my work shows that human keratinocytes in vitro have two, and only two, modes of proliferation: a stochastic mode that is insensitive to external EGF signalling, and a EGF-sensitive exponential mode. Additionally, proliferation during wound repair can occur with stochastically dividing progenitors, and does not obligate stem cell recruitment in vivo.
Subjects/Keywords: Research Subject Categories::MEDICINE::Morphology, cell biology, pathology::Cell biology::Medical cell biology; stem cells
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APA (6th Edition):
Roshan, A. (2014). Stochasticity and order: studies of keratinocyte proliferation. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/252966https://www.repository.cam.ac.uk/bitstream/1810/252966/3/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/4/Roshan_2014_PhD-37461.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/6/Roshan_2014_Agreement.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/5/Roshan_2014_PhD-37461.pdf.jpg ; https://www.repository.cam.ac.uk/bitstream/1810/252966/7/Roshan_2014_Agreement.pdf.jpg
Chicago Manual of Style (16th Edition):
Roshan, Amit. “Stochasticity and order: studies of keratinocyte proliferation.” 2014. Doctoral Dissertation, University of Cambridge. Accessed February 28, 2021.
https://www.repository.cam.ac.uk/handle/1810/252966https://www.repository.cam.ac.uk/bitstream/1810/252966/3/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/4/Roshan_2014_PhD-37461.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/6/Roshan_2014_Agreement.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/5/Roshan_2014_PhD-37461.pdf.jpg ; https://www.repository.cam.ac.uk/bitstream/1810/252966/7/Roshan_2014_Agreement.pdf.jpg.
MLA Handbook (7th Edition):
Roshan, Amit. “Stochasticity and order: studies of keratinocyte proliferation.” 2014. Web. 28 Feb 2021.
Vancouver:
Roshan A. Stochasticity and order: studies of keratinocyte proliferation. [Internet] [Doctoral dissertation]. University of Cambridge; 2014. [cited 2021 Feb 28].
Available from: https://www.repository.cam.ac.uk/handle/1810/252966https://www.repository.cam.ac.uk/bitstream/1810/252966/3/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/4/Roshan_2014_PhD-37461.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/6/Roshan_2014_Agreement.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/5/Roshan_2014_PhD-37461.pdf.jpg ; https://www.repository.cam.ac.uk/bitstream/1810/252966/7/Roshan_2014_Agreement.pdf.jpg.
Council of Science Editors:
Roshan A. Stochasticity and order: studies of keratinocyte proliferation. [Doctoral Dissertation]. University of Cambridge; 2014. Available from: https://www.repository.cam.ac.uk/handle/1810/252966https://www.repository.cam.ac.uk/bitstream/1810/252966/3/license.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/4/Roshan_2014_PhD-37461.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/6/Roshan_2014_Agreement.pdf.txt ; https://www.repository.cam.ac.uk/bitstream/1810/252966/5/Roshan_2014_PhD-37461.pdf.jpg ; https://www.repository.cam.ac.uk/bitstream/1810/252966/7/Roshan_2014_Agreement.pdf.jpg
6.
Rollins, Joseph Daniel.
Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer.
Degree: MS, Biological Sciences, 2017, Encompass Digital Archive, Eastern Kentucky University
URL: https://encompass.eku.edu/etd/463
► Cancer has always plagued humans and animals alike. Throughout history, it has been called many names, been the center of myths and legends, and…
(more)
▼ Cancer has always plagued humans and animals alike. Throughout history, it has been called many names, been the center of myths and legends, and has been ritualistically studied in hopes of finding a cure. Did it arise from sin, or perhaps a curse, or did it simply happen at random? Cancer's underlying cause has, until recently, been eluding doctors and scientists for decades, leaving in its wake the vital need to dismantle the shroud of secrecy surrounding it. But what exactly is cancer, and more importantly, why is there such urgency in deciphering its genetic anomaly? Cancer is, at its basic definition, the rapid and uncontrollable proliferation of cells. These cells eventually become a mass, feeding off nutrients from other organs, eventually invading other organ systems and overtaking the body. Once cancer has reached this stage, surgical intervention is no longer effective, leaving other methods necessary to eliminate cellular growth. Although chemotherapy has had a relatively short history, it has led to a diverse and complex field of treatment options that holds the potential to attenuate aggressive cancers. Older generations of chemotherapy target specific phases of the cell cycle, to arrest development, or they target the DNA itself. New generations of chemotherapeutics looked to overcome problems that the first had left: improved selectivity, reduced side effects, increased potency, and the ability to target cancer cells more precisely. As such, the first phase in this project aimed to attenuate the proliferation and spread of cancer by targeting enzymes crucial for cell division and migration, (iPLA2β and MMP-9), with a suicide inhibitor Bromoenol Lactone (BEL). Although this approach did result in significant attenuation of tumor growth and migration, it lacked the ability to be highly selective and the therapeutic index left something to be desired. With that in mind, the second phase of this project aimed to circumvent the problems with the previous chemotherapeutic, as well as traditional agents, by targeting a receptor that is vastly overexpressed on the surface of cancer cells. It has been previously found that Luteinizing Hormone Releasing Hormone (LHRH) receptors are overexpressed in many different cancer types, thus giving a new target to deliver higher concentrations of drug while sparing normal tissues. By linking a molecule of this peptide with traditional platinum based chemotherapy, Cisplatin, cancer cells were easily targeted and selectively attacked. Results from preliminary pre-clinical trials with this newly synthesized drug, named Pt-Mal-LHRH, showed a significant decrease in cancer cell viability, greater cellular uptake of the drug compared to others, significant tumor volume reduction, and the ability to spare normal cells. With such promising results, this Pt-Mal-LHRH leaves the hope for a new type of targeted and selective drug that can destroy cancer cells while sparring healthy tissue. Future directions of this project include continuing with pre-clinical trials and expanding…
Subjects/Keywords: Cancer; Chemotherapy; Pharmacology; Cancer Biology; Medical Cell Biology; Medical Pharmacology
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APA (6th Edition):
Rollins, J. D. (2017). Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer. (Masters Thesis). Encompass Digital Archive, Eastern Kentucky University. Retrieved from https://encompass.eku.edu/etd/463
Chicago Manual of Style (16th Edition):
Rollins, Joseph Daniel. “Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer.” 2017. Masters Thesis, Encompass Digital Archive, Eastern Kentucky University. Accessed February 28, 2021.
https://encompass.eku.edu/etd/463.
MLA Handbook (7th Edition):
Rollins, Joseph Daniel. “Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer.” 2017. Web. 28 Feb 2021.
Vancouver:
Rollins JD. Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer. [Internet] [Masters thesis]. Encompass Digital Archive, Eastern Kentucky University; 2017. [cited 2021 Feb 28].
Available from: https://encompass.eku.edu/etd/463.
Council of Science Editors:
Rollins JD. Development Of Novel Breast Cancer Chemotherapeutics Directed Towards The Attenuation Of Metastatic And Chemo-Resistant Breast Cancer. [Masters Thesis]. Encompass Digital Archive, Eastern Kentucky University; 2017. Available from: https://encompass.eku.edu/etd/463
Virginia Commonwealth University
7.
Quinn, Bridget A.
Novel Therapeutic Strategies for Pancreatic Cancer.
Degree: PhD, Human Genetics, 2014, Virginia Commonwealth University
URL: https://doi.org/10.25772/T39H-KJ31
;
https://scholarscompass.vcu.edu/etd/4671
► Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available…
(more)
▼ Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of the anti-apoptotic Bcl-2 proteins, and Minocycline, a commonly used antibiotic, show potent synergy when used in combination in both pancreatic cancer cells and in multiple immune-deficient and immune-competent mouse models of pancreatic cancer. Sabutoclax alone is capable of inducing
cell cycle arrest and apoptosis in cells and its cytotoxicity is enhanced significantly when combined with Minocycline. This combination results in the loss of Stat3 activation both
in vitro and
in vivo, which is essential for its toxicity. It also inhibits tumor growth and prolongs survival in the KPC transgenic mouse model of pancreatic cancer. Also presented here are studies that demonstrate efficacy
in vivo of modified versions of Gemcitabine and Paclitaxel. These drugs are linked to a peptide that shows specificity for the EphA2 receptor, which is overexpressed on the surface of pancreatic cancer cells and only minimally on normal cells. This peptide results in increased cellular uptake of drug, as it is bypassing its normal mechanism of entry. These normal mechanisms are often dysregulated in cancer, leading to decreased uptake and drug resistance. The use of these modified drugs show significantly increased tumor growth inhibition as compared to the parent drug alone. Finally, we provide data on the characterization of a novel transgenic mouse model of pancreatic cancer. This model, the Pan Met View (PMV) mouse, combines the commonly used KPC transgenic mouse model of pancreatic cancer and a mouse that expresses a Luciferase reporter gene under the control of the cancer-specific promoter, CCN1. Our data shows that double transgenic PMV mice can now be used to follow primary tumor and metastasis development in real time by Bioluminescent imaging (BLI) through disease progression and potentially therapy. This strategy will enhance the use of genetically engineered mouse models (GEMMS) to study cancer initiation and progression with potential to non-invasively monitor therapy. These chapters present novel and exciting data that have the potential to open multiple avenues of translational study and result in significant advances in pancreatic cancer therapy.
Advisors/Committee Members: Paul B. Fisher.
Subjects/Keywords: Medical Cell Biology; Medical Genetics; Neoplasms; Oncology; Translational Medical Research
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APA (6th Edition):
Quinn, B. A. (2014). Novel Therapeutic Strategies for Pancreatic Cancer. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/T39H-KJ31 ; https://scholarscompass.vcu.edu/etd/4671
Chicago Manual of Style (16th Edition):
Quinn, Bridget A. “Novel Therapeutic Strategies for Pancreatic Cancer.” 2014. Doctoral Dissertation, Virginia Commonwealth University. Accessed February 28, 2021.
https://doi.org/10.25772/T39H-KJ31 ; https://scholarscompass.vcu.edu/etd/4671.
MLA Handbook (7th Edition):
Quinn, Bridget A. “Novel Therapeutic Strategies for Pancreatic Cancer.” 2014. Web. 28 Feb 2021.
Vancouver:
Quinn BA. Novel Therapeutic Strategies for Pancreatic Cancer. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2014. [cited 2021 Feb 28].
Available from: https://doi.org/10.25772/T39H-KJ31 ; https://scholarscompass.vcu.edu/etd/4671.
Council of Science Editors:
Quinn BA. Novel Therapeutic Strategies for Pancreatic Cancer. [Doctoral Dissertation]. Virginia Commonwealth University; 2014. Available from: https://doi.org/10.25772/T39H-KJ31 ; https://scholarscompass.vcu.edu/etd/4671
Virginia Commonwealth University
8.
Alsharief, Fahda Fawaz.
Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility.
Degree: MS, Molecular Biology and Genetics, 2017, Virginia Commonwealth University
URL: https://doi.org/10.25772/2VEH-V660
;
https://scholarscompass.vcu.edu/etd/5018
► The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight…
(more)
▼ The integrity and barrier properties of intestinal epithelium are determined by specialized adhesive structures known as intercellular junctions; composed of adherens junctions (AJs), tight junctions (TJs) and focal adhesions that mediate
cell-cell and
cell matrix interactions, respectively. These two types of epithelial
cell adhesions regulate each other during disruption and restitution of the epithelial barrier. Inflammatory cytokines such as interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are elevated during intestinal inflammation. The most notable effects of IFNγ and TNFα on intestinal epithelial homeostasis involve disruption of apical junctions and attenuation of
cell migration. Although molecular mechanisms underlying these effects remain poorly understood, expressional downregulation of different adhesion proteins may play a major role in the cytokine-dependent disruption of the intestinal epithelial barriers. This thesis is based on the hypothesis that inhibition of the protein translation initiation machinery promotes the disruption of the intestinal epithelial barrier and attenuates epithelial restitution during mucosal inflammation. This study was focused on two eukaryotic translation initiation factors, eIF4G1 and eIF4G2, which play essential roles in the regulation of cap-dependent protein translation. Expression of both translation initiation factors was dramatically downregulated in model intestinal epithelial
cell monolayers treated with IFNγ and TNFα in parallel to cytokine-induced disruption of the epithelial barrier. siRNA or shRNA-mediated downregulation of either eIF4G1, or eIF4G2 increased permeability of well-differentiated SK-CO15 intestinal epithelial
cell monolayers and decreased expression of different adherens junction and tight junction proteins. Furthermore depletion of these translation initiating factors inhibits different modes of migration (wound healing and transfilter migration) of stem-
cell like and well-differentiated intestinal epithelial cells. These findings suggest that eukaryotic translation initiation factors of the eIF4G family play unique roles in regulating integrity and restitution of the intestinal epithelial barrier. Downregulation of these translation initiating factors may mediate disruption of the intestinal epithelial barriers during mucosal inflammation.
Advisors/Committee Members: Andrei Ivanov.
Subjects/Keywords: Medical Biophysics; Medical Cell Biology; Medical Genetics; Physiological Processes
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APA (6th Edition):
Alsharief, F. F. (2017). Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility. (Thesis). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/2VEH-V660 ; https://scholarscompass.vcu.edu/etd/5018
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Alsharief, Fahda Fawaz. “Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility.” 2017. Thesis, Virginia Commonwealth University. Accessed February 28, 2021.
https://doi.org/10.25772/2VEH-V660 ; https://scholarscompass.vcu.edu/etd/5018.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Alsharief, Fahda Fawaz. “Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility.” 2017. Web. 28 Feb 2021.
Vancouver:
Alsharief FF. Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility. [Internet] [Thesis]. Virginia Commonwealth University; 2017. [cited 2021 Feb 28].
Available from: https://doi.org/10.25772/2VEH-V660 ; https://scholarscompass.vcu.edu/etd/5018.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Alsharief FF. Role of Translation Initiation in Regulation of Epithelial Junctions and Cell Motility. [Thesis]. Virginia Commonwealth University; 2017. Available from: https://doi.org/10.25772/2VEH-V660 ; https://scholarscompass.vcu.edu/etd/5018
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
9.
Waight, Andrew Bryan.
Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel.
Degree: 2010, New York University
URL: http://pqdtopen.proquest.com/#viewpdf?dispub=3408358
► Transport of charged and polar solutes across membranes is fundamental to cellular organisms, and studies on these processes are elemental to the understanding of…
(more)
▼ Transport of charged and polar solutes across membranes is fundamental to cellular organisms, and studies on these processes are elemental to the understanding of a wide variety of biological fields ranging from cellular metabolism to neurology. Integral membrane channel proteins represent basic systems of solute transport, catalyzing the translocation of their substrates down a concentration gradient without the need for external energy sources. Nevertheless, channel proteins exhibit a high degree of substrate selectivity and yet can facilitate ionic flux rates that often approach the limits of diffusion. In anaerobic environments, microorganisms convert up to one third of metabolized glucose into the simple carboxylate ion, formate. In the <i> Escherichia coli</i> bacterium, this metabolite is transported across the inner membrane through the FocA protein, which serves as the founding member in the formate/nitrite transporter (FNT) family encompassing over 1500 homologues in bacteria, yeast and simple eukaryotes. Additionally, a nitrite transporting variant of the FNT family has been shown in mice to play a role in <i>Salmonella</i> pathogenesis and may provide a paradigm for bacterial defense against reactive nitrogen species released by the host. High resolution structural data for any FNT family members has been unavailable, and the mechanism of substrate translocation has not been determined. In this work, the successful purification, crystallization and subsequent structure elucidation of the novel FocA protein from <i>Vibrio cholerae</i> structure to 2.1 Å resolution is described. A supplemental crystal structure shows the location of two substrate molecules near a central and conserved region of the cytoplasmic pore, and biochemical assays support activity of the protein. The tertiary protein structure exhibits a homopentameric organization, however the monomeric topology and fold is represented in the tetrameric aquaporin family of water and glycerol channels. Within the crystallographic pentamer, a conserved half-membrane spanning pore helix adopts different conformations. In addition, the location of substrate molecules in this region indicates that the FocA selectivity filter is formed on the cytoplasmic side of the protein and that lateral gating of the pore region is activated by the presence of formate molecules. A hypothesis for selectivity and gating in the FNT family is presented.
Subjects/Keywords: Biology, Cell; Chemistry, Biochemistry; Biophysics, Medical
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MLA ·
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CSE |
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APA (6th Edition):
Waight, A. B. (2010). Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel. (Thesis). New York University. Retrieved from http://pqdtopen.proquest.com/#viewpdf?dispub=3408358
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Waight, Andrew Bryan. “Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel.” 2010. Thesis, New York University. Accessed February 28, 2021.
http://pqdtopen.proquest.com/#viewpdf?dispub=3408358.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Waight, Andrew Bryan. “Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel.” 2010. Web. 28 Feb 2021.
Vancouver:
Waight AB. Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel. [Internet] [Thesis]. New York University; 2010. [cited 2021 Feb 28].
Available from: http://pqdtopen.proquest.com/#viewpdf?dispub=3408358.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Waight AB. Structure and mechanism of the FocA formate channel| Discovery of an organic ion channel. [Thesis]. New York University; 2010. Available from: http://pqdtopen.proquest.com/#viewpdf?dispub=3408358
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Loyola University Chicago
10.
Frazier-Jessen, Michelle Rene.
The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation.
Degree: PhD, Cell Biology, Neurobiology and
Anatomy, 1996, Loyola University Chicago
URL: https://ecommons.luc.edu/luc_diss/3407
Subjects/Keywords: Medical Cell Biology
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APA (6th Edition):
Frazier-Jessen, M. R. (1996). The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation. (Doctoral Dissertation). Loyola University Chicago. Retrieved from https://ecommons.luc.edu/luc_diss/3407
Chicago Manual of Style (16th Edition):
Frazier-Jessen, Michelle Rene. “The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation.” 1996. Doctoral Dissertation, Loyola University Chicago. Accessed February 28, 2021.
https://ecommons.luc.edu/luc_diss/3407.
MLA Handbook (7th Edition):
Frazier-Jessen, Michelle Rene. “The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation.” 1996. Web. 28 Feb 2021.
Vancouver:
Frazier-Jessen MR. The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation. [Internet] [Doctoral dissertation]. Loyola University Chicago; 1996. [cited 2021 Feb 28].
Available from: https://ecommons.luc.edu/luc_diss/3407.
Council of Science Editors:
Frazier-Jessen MR. The Effect of Estrogen in a Murine Model of Peritoneal
Adhesion Formation. [Doctoral Dissertation]. Loyola University Chicago; 1996. Available from: https://ecommons.luc.edu/luc_diss/3407
Harvard University
11.
Powers, Robert Edward.
Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network.
Degree: PhD, 2018, Harvard University
URL: http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050074
► Membrane-bound organelles, a defining feature of eukaryotic cells, display a diverse set of characteristic shapes that range from highly spherical, to flattened sheets, and even…
(more)
▼ Membrane-bound organelles, a defining feature of eukaryotic cells, display a diverse set of characteristic shapes that range from highly spherical, to flattened sheets, and even thin tubules. Therefore, how the characteristic shape of an organelle is generated, maintained, and modified is a fundamental question in eukaryotic
cell biology. A powerful model system for studying organelle morphology is the endoplasmic reticulum (ER), which consists of a network of membrane sheets and tubules that extend throughout a
cell. Previous studies have shown that the high membrane curvature of the tubules is generated and stabilized by integral membrane proteins of the reticulon and Yop1/REEP families and that individual tubules are fused together by the dynamin-like GTPases Atlastin (in metazoans) and Sey1p/RHD3 (yeast/plants). Although an in vitro assay for ER network formation has been developed using Xenopus egg extracts, the minimal set of components needed to form a tubular ER network has not been identified, and whether these minimal components allow for the ER dynamics observed in vivo is not known.
In this thesis, I will focus on the molecular mechanisms responsible for shaping the endoplasmic reticulum and offer insight into how these mechanisms give rise to the distinct tubular architecture observed for particular subdomains of the endoplasmic reticulum. I demonstrate that the minimal set of proteins needed to form the tubular ER network consists solely of a curvature-stabilizing protein and a membrane-fusing protein. Co-reconstitution of Saccharomyces cerevisiae Sey1p with a number of different curvature-stabilizing proteins of the reticulon and Yop1/REEP families yield proteoliposomes that, when incubated with GTP, form tubular networks that are nearly indistinguishable from those observed in the extracts of Xenopus laevis eggs. Furthermore, these reconstituted networks have the same dynamic behaviors as ER networks in cells, including junction sliding and ring closure. Finally, the integrity of the synthetic network is dependent upon the GTPase activity of the membrane-fusing protein, as incubation of pre-formed reconstituted networks with GTPγS leads to rapid network disassembly. Taken together, these results demonstrate that the tubular ER can be generated by a surprisingly small set of proteins and represents an energy-dependent steady state between formation and disassembly.
I also describe my initial steps toward obtaining a structure of a curvature-stabilizing protein of the Yop1/REEP family using x-ray crystallography. The lack of an atomic-resolution structure of any of these proteins has left their exact mechanism of curvature generation and stabilization unknown. Unfortunately, given their small size and lack of hydrophilic surfaces, the Yop1/REEP proteins represent a difficult target for structural studies. To this end, I sought to use new tools that have been adapted for membrane protein crystallization to attempt to obtain a structure of the protein REEP5. These tools included lipidic cubic phase…
Advisors/Committee Members: Gaudet, Rachelle (committee member), Kruse, Andrew C. (committee member), Liao, Maofu (committee member), Hogle, James M. (committee member).
Subjects/Keywords: Biophysics, Medical; Chemistry, Biochemistry; Biology, Cell
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CSE |
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APA (6th Edition):
Powers, R. E. (2018). Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network. (Doctoral Dissertation). Harvard University. Retrieved from http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050074
Chicago Manual of Style (16th Edition):
Powers, Robert Edward. “Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network.” 2018. Doctoral Dissertation, Harvard University. Accessed February 28, 2021.
http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050074.
MLA Handbook (7th Edition):
Powers, Robert Edward. “Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network.” 2018. Web. 28 Feb 2021.
Vancouver:
Powers RE. Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network. [Internet] [Doctoral dissertation]. Harvard University; 2018. [cited 2021 Feb 28].
Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050074.
Council of Science Editors:
Powers RE. Molecular Mechanisms of the Formation and Maintenance of the Tubular Endoplasmic Reticulum Network. [Doctoral Dissertation]. Harvard University; 2018. Available from: http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050074
University of Lund
12.
Moraghebi, Roksana.
The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation.
Degree: 2017, University of Lund
URL: https://lup.lub.lu.se/record/f0fcdff9-cdd7-4308-828f-827992336095
;
https://portal.research.lu.se/ws/files/29953955/Roksana_Moraghebi_Thesis.pdf
► Human pluripotent stem cells (PSCs) are widely used for studying embryonic development, disease modelling, drug discovery and cell therapy development. Using human PSCs as a…
(more)
▼ Human pluripotent stem cells (PSCs) are widely used
for studying embryonic development, disease modelling, drug
discovery and cell therapy development. Using human PSCs as a model
has significantly contributed to our understanding of embryonic
development and elucidating novel pathological mechanisms as well
as developing new drugs. However, there are significant genetic and
epigenetic variations among hPSCs which can potentially affect
their utility and differentiation potential, and thus undermine
their applicability for downstream applications. In addition,
female hPSCs under conventional culture conditions are
epigenetically unstable, which is a major concern for disease
modeling. The heterogeneity among hPSCs may be inherited from
source cell populations, introduced during reprograming or
accumulated during culture. Regardless of the source of this
heterogeneity and instability, if human PSCs are to be used in
embryonic development and disease modeling studies or regenerative
medicine, these variations need to be understood and perhaps
adjusted for. Human PSCs can potentially differentiate into all
cells of the body including hematopoietic cells, and thus hold
great promise for hematopoietic stem cell transplantation or
transfusion therapies. However, the heterogeneity among hPSCs can
affect their hematopoietic differentiation potential. For example,
the level of IGF2 expression in hiPSCs is correlated with their
hematopoietic commitment capacity, and diversity in DNA methylation
patterns of hiPSCs is associated with their hematopoietic
maturation capacity. It has been reported that differentiation
potential of iPSC lines is skewed in favor of their source cell
lineage. For example, iPSC lines derived from blood cells have a
greater ability to differentiate towards blood cell lineages
compared to the lines that are derived from skin cells. In paper I,
we evaluate the influence of donor and cell type on the epigenome
and hematopoietic differentiation potential of iPSC lines derived
from blood and fibroblast cells of multiple donors. We demonstrate
that donor genetic background has a much greater influence on the
epigenome and hematopoietic differentiation potential of iPSC
lines. Due to the large impact of donor on differentiation
potential, in paper II we propose the establishment of a broad
spectrum HLA type-matched iPSC bank derived from a broad donor base
of term amniotic fluid derived cells in connection to planned
caesarean section deliveries. Term amniotic fluid cells, being from
a neonatal source have likely accumulated fewer genetic mutations
compared to adult sources and thus are a better cell source for
iPSC generation and will reduce variations among hiPSC lines. It
has been also suggested that erosion of the transcriptionally
inactive X chromosome in female PSCs under conventional culture
condition is correlated with poor differentiation propensity,
including hematopoietic differentiation potential. In paper III, we
evaluate the effects of epigenetic instability of female hiPSC on
their hematopoietic…
Subjects/Keywords: Medical Genetics; Cell and Molecular Biology
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APA (6th Edition):
Moraghebi, R. (2017). The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation. (Doctoral Dissertation). University of Lund. Retrieved from https://lup.lub.lu.se/record/f0fcdff9-cdd7-4308-828f-827992336095 ; https://portal.research.lu.se/ws/files/29953955/Roksana_Moraghebi_Thesis.pdf
Chicago Manual of Style (16th Edition):
Moraghebi, Roksana. “The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation.” 2017. Doctoral Dissertation, University of Lund. Accessed February 28, 2021.
https://lup.lub.lu.se/record/f0fcdff9-cdd7-4308-828f-827992336095 ; https://portal.research.lu.se/ws/files/29953955/Roksana_Moraghebi_Thesis.pdf.
MLA Handbook (7th Edition):
Moraghebi, Roksana. “The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation.” 2017. Web. 28 Feb 2021.
Vancouver:
Moraghebi R. The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation. [Internet] [Doctoral dissertation]. University of Lund; 2017. [cited 2021 Feb 28].
Available from: https://lup.lub.lu.se/record/f0fcdff9-cdd7-4308-828f-827992336095 ; https://portal.research.lu.se/ws/files/29953955/Roksana_Moraghebi_Thesis.pdf.
Council of Science Editors:
Moraghebi R. The Effects of Genetic and Epigenetic Variation on Human
Pluripotent Stem Cell Differentiation. [Doctoral Dissertation]. University of Lund; 2017. Available from: https://lup.lub.lu.se/record/f0fcdff9-cdd7-4308-828f-827992336095 ; https://portal.research.lu.se/ws/files/29953955/Roksana_Moraghebi_Thesis.pdf
McMaster University
13.
Caron, Nicholas S.
Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease.
Degree: PhD, 2014, McMaster University
URL: http://hdl.handle.net/11375/15344
► Huntington’s disease (HD) is a progressive, neurodegenerative disorder that leads to the selective loss of neurons in the striatum and the cerebral cortex. HD…
(more)
▼ Huntington’s disease (HD) is a progressive, neurodegenerative disorder that leads to the selective loss of neurons in the striatum and the cerebral cortex. HD is caused by a CAG trinucleotide repeat expansion beyond the normal length in the IT15 (Htt) gene. The CAG stretch codes for an elongated polyglutamine tract within the amino‐terminus of the huntingtin protein. Polyglutamine tracts with lengths exceeding 37 repeats cause HD whereas repeat lengths below do not. This phenomenon has plagued the HD community since the discovery of the gene in 1993. In this thesis, we sought to elucidate the molecular mechanism by which huntingtin becomes toxic at polyglutamine lengths above 37. Using Förster resonance energy transfer (FRET) techniques, we describe an intramolecular proximity between the first 17 residues (N17) and the proline-rich regions, which flank the polyglutamine tract of huntingtin. We report that we can precisely measure differences between the conformations adopted by the huntingtin protein with polyglutamine tracts below and above the pathogenic repeat threshold of 37 repeats. Our data supports the hypothesis that polyglutamine tracts below the pathogenic threshold can act as a flexible hinge allowing the N17 domain to freely fold back upon huntingtin and come into close 3D proximity with the polyproline region. This flexibility is lost in polyglutamine tracts with >37 repeats resulting in a diminished spatial proximity between N17 and the polyproline domain.
Doctor of Philosophy (PhD)
Advisors/Committee Members: Truant, Ray, David Andrews, Jon Draper, Biochemistry and Biomedical Sciences.
Subjects/Keywords: Huntington's disease; huntingtin; biosensor; FRET; Medical Cell Biology; Medical Molecular Biology; Nervous System Diseases; Medical Cell Biology
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APA (6th Edition):
Caron, N. S. (2014). Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/15344
Chicago Manual of Style (16th Edition):
Caron, Nicholas S. “Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease.” 2014. Doctoral Dissertation, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/15344.
MLA Handbook (7th Edition):
Caron, Nicholas S. “Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease.” 2014. Web. 28 Feb 2021.
Vancouver:
Caron NS. Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease. [Internet] [Doctoral dissertation]. McMaster University; 2014. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/15344.
Council of Science Editors:
Caron NS. Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease. [Doctoral Dissertation]. McMaster University; 2014. Available from: http://hdl.handle.net/11375/15344
McMaster University
14.
Collins, AF Celeste.
The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death.
Degree: MSc, 2013, McMaster University
URL: http://hdl.handle.net/11375/15325
► Pleckstrin homology like domain family A, member 1 (PHLDA1) is a member of the PHLDA family of homologous proteins recognized for their role in…
(more)
▼ Pleckstrin homology like domain family A, member 1 (PHLDA1) is a member of the PHLDA family of homologous proteins recognized for their role in apoptotic cell death. PHLDA1 was first reported as a proapoptotic factor involved in Fas-mediated T-cell apoptosis. The role of this protein with regards to apoptosis remains poorly understood, with literature demonstrating both proapoptotic and antiapoptotic functions in a cell and/or pathway specific manner. Intracellular localization may account for the apoptotic potential of this protein, with nuclear accumulation of PHLDA1 increasing its apoptotic potential. We hypothesize that the functional regions of PHLDA1 including its localization signals (pNLS/pNES), pleckstrin homology like domain (PHLD), and PQ region direct cellular localization of PHLDA1, thereby regulating its apoptotic potential. In this thesis, well-established molecular and cellular approaches were utilized to better define the functional regions within PHLDA1 and to gain further understanding of the role of its localization on apoptosis. Using an EGFP fusion construct and leptomycin B, we confirmed that PHLDA1 contains a weak, CRM1-responsive NES. Using an EGFP-β-galactosidase fusion protein we examined the putative NLS of PHLDA1 and determined that it was not sufficient to direct nuclear localization. However, the PHLD was found to direct cellular localization, mirroring the distribution and punctate patterning of full length PHLDA1. Evidence of association of the PHLD with the membrane was confirmed using fluorescence and electron microscopy, and changes in cell morphology indicative of EMT were apparent following overexpression of the PHLD. Although previous reports have suggested that the PQ region of PHLDA1 is responsible for its proapoptotic function, its cellular localization was not clearly defined. Nuclear accumulation of the PQ region was found to be highly cytotoxic, indicating that it is sufficient to induce apoptosis and that its proapoptotic activity occurs within the nucleus. The findings of this thesis provide fresh insight into the functional regions of PHLDA1 and their respective contributions to the protein’s intracellular localization and apoptotic function, demonstrating that localization dictates the apoptotic potential of PHLDA1. This data provides a solid foundation for identifying the cellular mechanisms by which PHLDA1 influences the progression of chronic human diseases including diabetes, cancer and obesity.
Master of Science (MSc)
Advisors/Committee Members: Austin, Richard, Jeffrey Dickhout, Ray Truant, Medical Sciences (Blood and Cardiovascular).
Subjects/Keywords: PHLDA1; TDAG51; Medical Biochemistry; Medical Cell Biology; Medical Sciences; Reproductive and Urinary Physiology; Medical Biochemistry
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APA ·
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MLA ·
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APA (6th Edition):
Collins, A. C. (2013). The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/15325
Chicago Manual of Style (16th Edition):
Collins, AF Celeste. “The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death.” 2013. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/15325.
MLA Handbook (7th Edition):
Collins, AF Celeste. “The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death.” 2013. Web. 28 Feb 2021.
Vancouver:
Collins AC. The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death. [Internet] [Masters thesis]. McMaster University; 2013. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/15325.
Council of Science Editors:
Collins AC. The Functional Domains of PHLDA1: Modulation of Intracellular Localization Impacts Apoptotic Cell Death. [Masters Thesis]. McMaster University; 2013. Available from: http://hdl.handle.net/11375/15325
East Tennessee State University
15.
Hilton, Benjamin A.
Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans.
Degree: PhD, Biomedical Sciences, 2016, East Tennessee State University
URL: https://dc.etsu.edu/etd/3040
► Endogenous and exogenous agents that can damage DNA are a constant threat to genome stability in all living cells. In response, cells have evolved…
(more)
▼ Endogenous and exogenous agents that can damage DNA are a constant threat to genome stability in all living cells. In response, cells have evolved an array of mechanisms to repair DNA damage or to eliminate the cells damaged beyond repair. One of these mechanisms is nucleotide excision repair (NER) which is the major repair pathway responsible for removing a wide variety of bulky DNA lesions. Deficiency, or mutation, in one or several of the NER repair proteins is responsible for many diseases, including cancer. Prokaryotic NER involves only three proteins to recognize and incise a damaged site, while eukaryotic NER requires more than 25 proteins to efficiently recognize and incise a damaged site. XPC-RAD23B (XPC) is the damage recognition factor in eukaryotic global genome NER. The association rate of XPC to damaged DNA has been extensively studied; however, our data suggests that the dissociation of the XPC-DNA complex is the rate-limiting step in NER. The factor that verifies DNA-damage downstream of XPC is XPA. XPA also has been implicated in binding of ds-ssDNA junctions and has been found to bind at or near double-strand break sites in the premature aging syndrome Hutchinson-Gilford progeria (HGPS). This role for XPA is outside of its known function in NER and suggests that XPA may bind at collapsed replication forks in HGPS that are unprotected due to a lack of binding by replication proteins. Along with XPC and XPA, ataxia telangiectasia and Rad3-related (ATR) is activated in response to DNA damage and initiates the cell cycle checkpoint pathway to rescue cells from genomic instability. We found that ATR functions outside of its known role in the checkpoint signaling cascade. Our data demonstrate that ATR can rescue cells from apoptosis by inhibiting cytochrome c release at the mitochondria though direct interaction with the outer mitochondrial membrane and the proapoptotic protein tBid. The role of ATR in apoptosis is regulated by Pin1, which can change the structure of ATR at the backbone level. All of the results presented here suggest novel roles for DNA repair proteins in the maintenance of genome stability.
Subjects/Keywords: Nucleotide Excision Repair; UvrABC; XPC; XPA; ATR; Apoptosis; Biochemistry; Cancer Biology; Cell Biology; Medical Biochemistry; Medical Cell Biology; Molecular Biology
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APA (6th Edition):
Hilton, B. A. (2016). Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans. (Doctoral Dissertation). East Tennessee State University. Retrieved from https://dc.etsu.edu/etd/3040
Chicago Manual of Style (16th Edition):
Hilton, Benjamin A. “Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans.” 2016. Doctoral Dissertation, East Tennessee State University. Accessed February 28, 2021.
https://dc.etsu.edu/etd/3040.
MLA Handbook (7th Edition):
Hilton, Benjamin A. “Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans.” 2016. Web. 28 Feb 2021.
Vancouver:
Hilton BA. Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans. [Internet] [Doctoral dissertation]. East Tennessee State University; 2016. [cited 2021 Feb 28].
Available from: https://dc.etsu.edu/etd/3040.
Council of Science Editors:
Hilton BA. Investigation of Novel Functions for DNA Damage Response and Repair Proteins in Escherichia coli and Humans. [Doctoral Dissertation]. East Tennessee State University; 2016. Available from: https://dc.etsu.edu/etd/3040
McMaster University
16.
Wang, David Yu Chang.
Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli.
Degree: MSc, 2011, McMaster University
URL: http://hdl.handle.net/11375/11219
► In atherosclerotic plaques, macrophages ingest modified LDL and turn to foam cells. Others have shown that SR-BI expression levels inversely correlated with cellular cholesterol…
(more)
▼ In atherosclerotic plaques, macrophages ingest modified LDL and turn to foam cells. Others have shown that SR-BI expression levels inversely correlated with cellular cholesterol levels, and is independent of well characterized cholesterol sensing pathways; SREBP and LXR. Thus the mechanism of regulation of SR-BI is unclear. In this study, we showed that treating macrophage with agents known to increase cellular cholesterol levels, namely acLDL, LDL, MβCD:Cholesterol, resulted in reduction in HMGCoAR mRNA and SR-BI expression levels. In contrast, acLDL did not reduce SR-BI mRNA levels in macrophages from acLDL SR-A KO mice, demonstrating that acLDL mediate suppression of SR-BI was dependent on SR-A. Fucoidan, a known competitive inhibitor of acLDL binding to SR-A, and subsequent degradation, also suppressed SR-BI expression levels. Unlike acLDL, however, fucoidan induced mRNA levels corresponding to the pro-inflammatory genes iNOS and IL-6 mRNA levels, and its effects were not altered by the lack of SR-A. Instead, fucoidan mediated stimulation of iNOS and IL-6 and suppression of SR-BI mRNA levels was prevented by an anti-CD14 blocking antibody, demonstrating that the fucoidan mediated effects were dependent on CD14. Interleukin-15, a pro-inflammatory cytokine that binds to a distinct receptor, also induced iNOS and IL-6 mRNA levels and reduced SR-BI expression, suggesting that inflammatory signaling in general can reduce SR-BI expression levels. Treatment of macrophages with the lipoproteins acLDL, LDL or HDL suppressed the induction of iNOS and IL-6 mRNA by fucoidan or IL-15. Macrophages foam cells in an atherosclerotic plaque may have reduced SR-BI due to exposure with modified LDL or inflammatory cytokines or both in an atherosclerotic plaque. SR-BI expression in macrophages protects against atherosclerosis development. Our data suggests that modified lipoproteins as well as inflammatory stimuli suppress SR-BI expression in macrophages and this may contribute to their pro-apoptotic properties.
Master of Science (MSc)
Advisors/Committee Members: Trigatti, Bernardo L., Igdoura, Suleiman A., Truant, Ray, Biochemistry.
Subjects/Keywords: Atherosclerosis receptor cholesterol inflammation macrophage lipoprotein; Biochemistry; Biology; Cell Biology; Immunity; Medical Biochemistry; Medical Cell Biology; Medical Molecular Biology; Medical Sciences; Molecular Biology; Biochemistry
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APA (6th Edition):
Wang, D. Y. C. (2011). Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/11219
Chicago Manual of Style (16th Edition):
Wang, David Yu Chang. “Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli.” 2011. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/11219.
MLA Handbook (7th Edition):
Wang, David Yu Chang. “Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli.” 2011. Web. 28 Feb 2021.
Vancouver:
Wang DYC. Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli. [Internet] [Masters thesis]. McMaster University; 2011. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/11219.
Council of Science Editors:
Wang DYC. Regulation of macrophage SR-BI by lipoproteins and inflammatory stimuli. [Masters Thesis]. McMaster University; 2011. Available from: http://hdl.handle.net/11375/11219
University of Louisville
17.
Keith, Matthew C. L.
Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3).
Degree: PhD, 2016, University of Louisville
URL: 10.18297/etd/2390
;
https://ir.library.louisville.edu/etd/2390
► Over the last decade attempts at reducing morbidity and mortality of patients with chronic heart failure have been made via the development and implementation…
(more)
▼ Over the last decade attempts at reducing morbidity and mortality of patients with chronic heart failure have been made via the development and implementation of novel
cell based therapies. Substantial advances in
cell based therapies with indications of efficacy have been shown along with a robust safety profile. Despite these advances, there is a substantial unmet need for novel therapies, specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature. Accordingly, cardiac
cell-based therapies have gained attention. Various
cell-types have been utilized, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34
+ cells, and more recently, cardiosphere-derived cells and cardiac-derived c-kit positive progenitor cells. Early studies have suggested a potential of
cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. However, variability of results has been observed necessitating improvement of current methodologies related to optimizing the
cell type(s), infusion techniques, timing, dosage, acuity related to ischemic injury, and perhaps repeat dosing over time among others, all the while ensuring complete and total patient safety. Accordingly, present efforts and goals of my research are aimed at i.) Optimizing methodologies utilized within the recent phase I clinical trial (SCIPIO) that showed intracoronary infusion of 1 million c-kit positive cardiac progenitor cells was safe with indications of efficacy in cardiac repair, as well as, ii.) Development of a novel
cell based approach with a newly discovered cardiac
cell type. Within the present dissertation, I explored the impact of coronary stop-flow on cardiac retention of intracoronarily infused c-kit positive cardiac progenitor cells given that balloon inflation in a non-stented coronary artery is inherently dangerous, especially in already damaged hearts. I demonstrate that intracardiac retention with or without stop-flow is equivalent and balloon inflation confers an undue risk to patients. Furthermore, I investigated the safety of intracoronary infusion of 20 million c-kit positive cardiac progenitor cells in pigs, an equivalent dose 40 times larger than was used in the SCIPIO trial. High dose of cells delivered intracoronarily is safe and does not result in myocardial injury or functional deficit. Therefore, larger doses may reasonably be utilized in future clinical trials. Finally, I describe a novel adult cardiac
cell type that maintains expression of an embryonic stem
cell associated marker, stage-specific embryonic antigen (SSEA)-3, resides within the native adult heart, and can be isolated and utilized for cardiac repair as a
cell based therapy.
Advisors/Committee Members: Bolli, Roberto, Joshua, Irving, Joshua, Irving, Schuschke, Dale, Maldonado, Claudio, Conklin, Daniel.
Subjects/Keywords: stem cell; cardiac repair; cardiomyopathy; Medical Cell Biology
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APA (6th Edition):
Keith, M. C. L. (2016). Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3). (Doctoral Dissertation). University of Louisville. Retrieved from 10.18297/etd/2390 ; https://ir.library.louisville.edu/etd/2390
Chicago Manual of Style (16th Edition):
Keith, Matthew C L. “Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3).” 2016. Doctoral Dissertation, University of Louisville. Accessed February 28, 2021.
10.18297/etd/2390 ; https://ir.library.louisville.edu/etd/2390.
MLA Handbook (7th Edition):
Keith, Matthew C L. “Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3).” 2016. Web. 28 Feb 2021.
Vancouver:
Keith MCL. Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3). [Internet] [Doctoral dissertation]. University of Louisville; 2016. [cited 2021 Feb 28].
Available from: 10.18297/etd/2390 ; https://ir.library.louisville.edu/etd/2390.
Council of Science Editors:
Keith MCL. Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3). [Doctoral Dissertation]. University of Louisville; 2016. Available from: 10.18297/etd/2390 ; https://ir.library.louisville.edu/etd/2390
18.
Lasiter, Andrew D.
Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation.
Degree: MS, Biomedical Sciences, 2012, University of Tennessee Health Science Center
URL: https://dc.uthsc.edu/dissertations/150
► The ex vivo expansion of hematopoietic stem cells (HSCs) for transplantation has threefold importance: 1.) First, because of the rarity of stem cells there…
(more)
▼ The ex vivo expansion of hematopoietic stem cells (HSCs) for transplantation has threefold importance: 1.) First, because of the rarity of stem cells there often isn’t a sufficient supply obtainable from common sources for larger children and adults. 2.) Secondly, patient morbidity and time to hematopoietic reconstitution following myeloablative preconditioning is improved by administering a larger pool of HSCs. 3.) Lastly, gene therapies for hematological diseases still require a robust supply of HSCs to offset varying degrees of inefficiency in vector mediated transfection protocols. These reasons, and others, have been an impetus for many discoveries made within four primary subdivisions within the field of HSC expansion; culture media optimization, hematopoietic gene regulation, development of small molecular compounds, and use of induced pluripotent stem cells (iPSCs). This article is a review of the current trends in HSC expansion methodology and posits that the majority of the singling mechanisms involved can be explained by the collective contribution of activating and inhibitory gene expression products interacting through regulatory homeostatic process mediated by HSC sensing of key pathway dependent thresholds.
Advisors/Committee Members: Gerard P. Zambetti, Ph.D..
Subjects/Keywords: HSC; expansion; hematopoietic; model; stem; cell; Medical Cell Biology; Medical Sciences; Medicine and Health Sciences
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APA (6th Edition):
Lasiter, A. D. (2012). Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation. (Thesis). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/150
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lasiter, Andrew D. “Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation.” 2012. Thesis, University of Tennessee Health Science Center. Accessed February 28, 2021.
https://dc.uthsc.edu/dissertations/150.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lasiter, Andrew D. “Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation.” 2012. Web. 28 Feb 2021.
Vancouver:
Lasiter AD. Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation. [Internet] [Thesis]. University of Tennessee Health Science Center; 2012. [cited 2021 Feb 28].
Available from: https://dc.uthsc.edu/dissertations/150.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lasiter AD. Hematopoietic Stem Cell Threshold Sensing Controls Regulatory Pathways Facilitating Clinically Relevant Ex Vivo Expansion for Stem Cell Transplantation. [Thesis]. University of Tennessee Health Science Center; 2012. Available from: https://dc.uthsc.edu/dissertations/150
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Oxford
19.
Stranks, Amanda Jane.
Autophagy is indispensable for normal maturation and function of macrophages and neutrophils.
Degree: PhD, 2013, University of Oxford
URL: http://ora.ox.ac.uk/objects/uuid:f68e5f62-2e89-40be-abd8-816145cc1579
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604397
► Macrophages and neutrophils are vital cells of the immune system, performing crucial innate functions and bridging innate and adaptive immunity. However, inappropriate activation or poor…
(more)
▼ Macrophages and neutrophils are vital cells of the immune system, performing crucial innate functions and bridging innate and adaptive immunity. However, inappropriate activation or poor resolution of responses results in chronic inflammatory and autoimmune conditions due to accumulation of myeloid cells and uncontrolled cytokine production, as is commonly seen in the aging immune system. It is not clear what is required to maintain healthy myeloid cells throughout life or what links inflammation and myeloid dysfunction during the aging process. We have shown that autophagy, a vital intracellular degradation mechanism, is required for normal macrophage innate and adaptive immune functions such as phagocytosis and antigen presentation, as well as being an important regulator of the inflammatory response. Loss of autophagy also results in reduced surface antigen expression and increased glycolysis. We found that autophagy-deficient macrophages have a similar phenotype to aged macrophages. Furthermore, aged macrophages exhibit reduced autophagy compared with young macrophages, suggesting a link between reduced autophagy and acquisition of the aging macrophage phenotype. Finally, we show that autophagy plays a vital role in normal neutrophil differentiation, with autophagy-deficient neutrophils exhibiting altered nuclear morphology and aberrant granule formation. These data show that autophagy plays a critical role in the maintenance of essential macrophage homeostasis and functions by regulating inflammation and metabolism, thereby preventing immunosenescence. We postulate that autophagy modulation in macrophages and neutrophils may be used to prevent excess inflammation, such as in inflammatory and autoimmune diseases. Moreover, inflammation due to aging may potentially be delayed by induction or preservation of autophagy, which could improve immune responses and reduce the morbidity and mortality associated with “inflamm-aging”.
Subjects/Keywords: 616.07; Biology (medical sciences); Immunology; macrophage; autophagy; aging; metabolism; cell biology
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APA (6th Edition):
Stranks, A. J. (2013). Autophagy is indispensable for normal maturation and function of macrophages and neutrophils. (Doctoral Dissertation). University of Oxford. Retrieved from http://ora.ox.ac.uk/objects/uuid:f68e5f62-2e89-40be-abd8-816145cc1579 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604397
Chicago Manual of Style (16th Edition):
Stranks, Amanda Jane. “Autophagy is indispensable for normal maturation and function of macrophages and neutrophils.” 2013. Doctoral Dissertation, University of Oxford. Accessed February 28, 2021.
http://ora.ox.ac.uk/objects/uuid:f68e5f62-2e89-40be-abd8-816145cc1579 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604397.
MLA Handbook (7th Edition):
Stranks, Amanda Jane. “Autophagy is indispensable for normal maturation and function of macrophages and neutrophils.” 2013. Web. 28 Feb 2021.
Vancouver:
Stranks AJ. Autophagy is indispensable for normal maturation and function of macrophages and neutrophils. [Internet] [Doctoral dissertation]. University of Oxford; 2013. [cited 2021 Feb 28].
Available from: http://ora.ox.ac.uk/objects/uuid:f68e5f62-2e89-40be-abd8-816145cc1579 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604397.
Council of Science Editors:
Stranks AJ. Autophagy is indispensable for normal maturation and function of macrophages and neutrophils. [Doctoral Dissertation]. University of Oxford; 2013. Available from: http://ora.ox.ac.uk/objects/uuid:f68e5f62-2e89-40be-abd8-816145cc1579 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604397
University of Nevada – Las Vegas
20.
Ali Rodriguez, Rachel.
Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders.
Degree: MA, Psychology, 2019, University of Nevada – Las Vegas
URL: https://digitalscholarship.unlv.edu/thesesdissertations/3779
► Neurodevelopmental disorders (NDDs) affect more than 36% of children in countries with low- and middle- incomes (Boivin, 2015; McCoy, 2016). Interestingly, these heterogeneous disorders…
(more)
▼ Neurodevelopmental disorders (NDDs) affect more than 36% of children in countries with low- and middle- incomes (Boivin, 2015; McCoy, 2016). Interestingly, these heterogeneous disorders share a high incidence of epileptic seizures, suggesting a shared pathology. Seizures result when neuronal firing activity becomes disturbed and neurons fire excessively or in unregulated patterns. A key site in the control of neuronal firing patterns is the axon initial segment (AIS), where the local density of proteins and the morphology of the AIS in part determine the firing of neurons. We hypothesized that a disruption in the morphology and/or composition of the AIS can lead to the phenotypes seen in neurodevelopmental disorders, including seizures. To study this possibility, we performed morphological analyses of the AIS of cortical pyramidal neurons in mouse models of NDDs with a high incidence of epilepsy (Gabra2-1 and Mecp2+/-). Our results reveal morphological changes at the AIS of both, Gabra2-1 and Mecp2+/- mice, when compared to wild-type mice. Understanding neuropathological changes leading to these heterogeneous disorders will increase knowledge of the general underlying mechanisms thus contributing to the development of better therapies.
Advisors/Committee Members: Rochelle Hines, Dustin Hines, Jefferson Kinney, Murray Millar.
Subjects/Keywords: Biology; Cell Biology; Medical Neurobiology; Neuroscience and Neurobiology; Neurosciences
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APA (6th Edition):
Ali Rodriguez, R. (2019). Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders. (Masters Thesis). University of Nevada – Las Vegas. Retrieved from https://digitalscholarship.unlv.edu/thesesdissertations/3779
Chicago Manual of Style (16th Edition):
Ali Rodriguez, Rachel. “Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders.” 2019. Masters Thesis, University of Nevada – Las Vegas. Accessed February 28, 2021.
https://digitalscholarship.unlv.edu/thesesdissertations/3779.
MLA Handbook (7th Edition):
Ali Rodriguez, Rachel. “Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders.” 2019. Web. 28 Feb 2021.
Vancouver:
Ali Rodriguez R. Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders. [Internet] [Masters thesis]. University of Nevada – Las Vegas; 2019. [cited 2021 Feb 28].
Available from: https://digitalscholarship.unlv.edu/thesesdissertations/3779.
Council of Science Editors:
Ali Rodriguez R. Restructuring of the Axon Initial Segment in Mouse Models of Neurodevelopmental Disorders. [Masters Thesis]. University of Nevada – Las Vegas; 2019. Available from: https://digitalscholarship.unlv.edu/thesesdissertations/3779
University of Vermont
21.
McKenzie, Andrew J.
Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration.
Degree: PhD, Pharmacology, 2014, University of Vermont
URL: https://scholarworks.uvm.edu/graddis/273
► Ovarian cancer is the deadliest of all the gynecologic cancers and is known for its clinically occult and asymptomatic dissemination. Most ovarian malignancies are…
(more)
▼ Ovarian cancer is the deadliest of all the gynecologic cancers and is known for its clinically occult and asymptomatic dissemination. Most ovarian malignancies are diagnosed in the late stages of the disease and the high rate of morbidity is thought to be due, in part, to the highly metastatic nature of ovarian carcinomas. Cancer metastasis relies on the ability of cells to migrate away from primary tumors and invade into target tissues. Though the processes are distinct, cancer
cell invasion relies on the underlying migration machinery to invade target tissues.
Cell migration requires the coordinated effort of numerous spatially-regulated signaling pathways to extend protrusions, create new adhesion to the extracellular matrix (ECM), translocate the
cell body, and retract the
cell rear. Our lab established that the cyclic-AMP dependent protein kinase (PKA) subunits and enzymatic activity are localized to the leading edge of migrating cells and are required for
cell movement. Despite the importance for localized PKA activity during migration, neither its role in regulating ovarian cancer
cell migration and invasion nor the mechanism regulating leading edge PKA activity have been determined. Therefore, the objective of the enclosed work is to establish the importance of PKA for ovarian cancer
cell migration and invasion and elucidate the molecular mechanism governing leading edge PKA.
We demonstrate, for the first time, that PKA activity and spatial distribution through A-Kinase Anchoring Proteins (AKAPs) is required for efficient ovarian cancer
cell migration and invasion. Additionally, we establish a link between leading edge PKA activity in migrating cells, ECM stiffness sensing, and the regulation of both PKA activity and ovarian cancer
cell migration by the mechanical properties of the ECM. Finally, we delineate the hierarchy of
cell signaling events that regulate leading edge PKA activity and, ultimately, the migration of ovarian cancer cells. Specifically, we elucidate a mechanism where leading edge protrusions elicit leading edge calcium currents through the stretch-activated calcium channel (SACC) of the transient receptor potential family melastatin 7 (TrpM7) to activate actomyosin contractility. ECM substrate stiffness is sensed by the actin cytoskeleton and actomyosin contractility, which, in turn, regulates the activity of leading edge PKA activity. These studies have provided important insights into the regulation of
cell migration and have established the mechanistic details governing leading edge PKA activity during
cell migration.
Advisors/Committee Members: Alan K. Howe.
Subjects/Keywords: cancer; Cell migration; Cell signaling; Mechanobiology; metastasis; protein kinase A; Medical Cell Biology; Pharmacology
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APA (6th Edition):
McKenzie, A. J. (2014). Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration. (Doctoral Dissertation). University of Vermont. Retrieved from https://scholarworks.uvm.edu/graddis/273
Chicago Manual of Style (16th Edition):
McKenzie, Andrew J. “Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration.” 2014. Doctoral Dissertation, University of Vermont. Accessed February 28, 2021.
https://scholarworks.uvm.edu/graddis/273.
MLA Handbook (7th Edition):
McKenzie, Andrew J. “Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration.” 2014. Web. 28 Feb 2021.
Vancouver:
McKenzie AJ. Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration. [Internet] [Doctoral dissertation]. University of Vermont; 2014. [cited 2021 Feb 28].
Available from: https://scholarworks.uvm.edu/graddis/273.
Council of Science Editors:
McKenzie AJ. Mechanoregulation of leading edge PKA activity during ovarian cancer cell migration. [Doctoral Dissertation]. University of Vermont; 2014. Available from: https://scholarworks.uvm.edu/graddis/273
22.
Beamish, Christine A.
Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells.
Degree: 2014, University of Western Ontario
URL: https://ir.lib.uwo.ca/etd/2721
► Islet transplants have been successfully used as treatment for diabetes, but are limited by shortages of cadaveric insulin-producing β-cells. An alternate source may be the…
(more)
▼ Islet transplants have been successfully used as treatment for diabetes, but are limited by shortages of cadaveric insulin-producing β-cells. An alternate source may be the dedifferentiation, expansion, and subsequent redifferentiation of pancreatic islets or β-cells using in vitro techniques prior to transplant. Based on protocols which described the dedifferentiation of human islets to ductal-like cells, we hypothesized that neonatal mouse islets could be similarly dedifferentiated in vitro. Dedifferentiation techniques produced significant duct-like cells, but redifferentiation to insulin-expressing cells was limited. RIPCre;Z/AP+/+ mice were consequently utilized to lineage trace β-cell fate during culture by a human placental alkaline phosphatase (HPAP) reporter. The proportion of HPAP+ β-cells decreased significantly in culture, but the rare remaining cells expressed the ductal marker CK19. Flow cytometric sorting of β-cell subpopulations from whole pancreas showed that the HPAP+CK19+ cells had derived from insulin-positive, glucose-transporter-2-negative (Ins+Glut2-) cells, previously purported as insulin-expressing progenitor cells. In P7 mouse pancreas, these Ins+Glut2- cells represent 3.5% of all insulin+ cells, the majority of which were found outside of islets within β-cell aggregates (BCA, <5 β-cells). Ins+Glut2- cells demonstrated greater proliferation rates in vivo and in vitro as compared to Ins+Glut2+ cells, and a subset could differentiate into endocrine, ductal, and neural lineages. We sought to quantify the presence of these progenitor cells throughout life in both mouse and human pancreata, and how their abundance and location changes with age. The presence of Ins+Glut2- cells in human and mouse pancreas demonstrated similar distributions and iii ontogenies, being more abundant in BCA than islets at all ages sampled, and decreasing with age. Finally, neonatal rodents can regenerate β-cell mass after streptozotocin (STZ) exposure, but this response is mitigated in adulthood. As STZ accesses the β-cell via Glut2, we hypothesized that the β-cell regenerative capacity in early life involves mobilization of Ins+Glut2- cells, and used RIPCreER;Z/AP+/+ mice to trace these during damage and regeneration. We found that Ins+Glut2- cells indeed survived STZ exposure, and subsequently matured into Ins+Glut2+ cells. These Ins+Glut2- cells represent a transitional cell type, the majority of which contribute to pancreas maturation, and a subset of which retains multipotential lineage capability.
.
Subjects/Keywords: Beta cell; development; pancreas; differentiation; diabetes; GLUT2; progenitor cell; Medical Cell Biology
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Manager
APA (6th Edition):
Beamish, C. A. (2014). Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/2721
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Beamish, Christine A. “Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells.” 2014. Thesis, University of Western Ontario. Accessed February 28, 2021.
https://ir.lib.uwo.ca/etd/2721.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Beamish, Christine A. “Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells.” 2014. Web. 28 Feb 2021.
Vancouver:
Beamish CA. Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells. [Internet] [Thesis]. University of Western Ontario; 2014. [cited 2021 Feb 28].
Available from: https://ir.lib.uwo.ca/etd/2721.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Beamish CA. Pancreatic Beta Cell Plasticity and Involvement of Insulin-Expressing Progenitor Cells. [Thesis]. University of Western Ontario; 2014. Available from: https://ir.lib.uwo.ca/etd/2721
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
McMaster University
23.
DoHarris, Lindsay E.
Effects of Extreme Temperature on Airway Smooth Muscle Cell Death.
Degree: MSc, 2011, McMaster University
URL: http://hdl.handle.net/11375/11688
► Bronchial thermoplasty has recently been FDA approved as a novel therapy for use on adults suffering from severe asthma. The procedure uses radiofrequency energy…
(more)
▼ Bronchial thermoplasty has recently been FDA approved as a novel therapy for use on adults suffering from severe asthma. The procedure uses radiofrequency energy to heat the airways to 65°C for 10 s. This has been shown in dogs to lead to a reduction of airway smooth muscle mass and in humans to improve quality of life and asthma control. Early cellular reactions to this treatment are unclear; as well, there is limited information regarding thermal sensitivity of airway smooth muscle when exposed to extreme temperatures (50-65°C). We examined the cellular impact of bronchial thermoplasty by investigating the response of airway smooth muscle to heat by immersing bovine tracheal strips and bronchial segments in heated Krebs. We confirmed dramatically decreased functionality over the temperature range 50-60°C at 1 h and 24 h in all tissues. TUNEL analysis noted significant cell death in all tissues heated to 65°C and limited cell death in bronchial tissues treated with <55°C. Immunohistochemical analysis showed an effect of temperature on caspase 3 activation in bronchi; tracheal strips demonstrated co-localization of caspase 3 and TUNEL at 55°C but not 65°C. These data suggests that cell death of airway smooth muscle contributes to the cellular effects observed following heating to 65°C; at lower temperatures, cell death may be limited. We conclude that bronchial thermoplasty (heat treatment to 65°C for ~30 seconds) leads to a number of structural and functional changes in the airway smooth muscle, which culminate in marked loss of function and cell death.
Master of Health Sciences (MSc)
Advisors/Committee Members: Janssen, Luke, Inman, Mark, Cox, Gerard, Medical Sciences (Division of Physiology/Pharmacology).
Subjects/Keywords: Asthma; Airway Smooth Muscle; Bronchial Thermoplasty; Heat; Cell Death; Medical Molecular Biology; Medical Molecular Biology
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APA (6th Edition):
DoHarris, L. E. (2011). Effects of Extreme Temperature on Airway Smooth Muscle Cell Death. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/11688
Chicago Manual of Style (16th Edition):
DoHarris, Lindsay E. “Effects of Extreme Temperature on Airway Smooth Muscle Cell Death.” 2011. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/11688.
MLA Handbook (7th Edition):
DoHarris, Lindsay E. “Effects of Extreme Temperature on Airway Smooth Muscle Cell Death.” 2011. Web. 28 Feb 2021.
Vancouver:
DoHarris LE. Effects of Extreme Temperature on Airway Smooth Muscle Cell Death. [Internet] [Masters thesis]. McMaster University; 2011. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/11688.
Council of Science Editors:
DoHarris LE. Effects of Extreme Temperature on Airway Smooth Muscle Cell Death. [Masters Thesis]. McMaster University; 2011. Available from: http://hdl.handle.net/11375/11688
University of South Florida
24.
Nelson, Nadine D.
Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer.
Degree: 2015, University of South Florida
URL: https://scholarcommons.usf.edu/etd/5810
► Pancreatic cancer is one of the deadliest cancers with a five-year survival rate of 6%. Pancreatic cancer is resistant to conventional chemotherapy and is usually…
(more)
▼ Pancreatic cancer is one of the deadliest cancers with a five-year survival rate of 6%. Pancreatic cancer is resistant to conventional chemotherapy and is usually diagnosed at late stages. Current treatment options have minimal effects in extending patients' lives beyond 10 months. One significant limitation in developing treatments to combat pancreatic cancer is its immunosuppressive microenvironment. Pancreatic cancer secretes factors that activate immunosuppressive cells, such as regulatory T cells (Tregs). These Tregs suppress effector CD4+ and CD8+ T cell anti-tumor immune responses. Therefore, novel treatment options to reduce Treg-mediated immune suppression and increase the numbers and functions of CD4+ and CD8+ T cells are paramount to enhance anti-tumor immunity in pancreatic cancer tumor-bearing (TB) hosts.
The alternatively spliced transcription factor Ikaros is essential for lymphocyte development and is considered a tumor suppressor in T cells. Ikaros' protein stability and function are regulated by its phosphorylation and dephosphorylation by protein kinase CK2 and phosphatase 1 (PP1), respectively. Mutations and functional inactivation of Ikaros have mainly been investigated in T cell leukemias and lymphomas. In this dissertation, we investigated the role of Ikaros in regulating T cell homeostasis in murine pancreatic cancer.
In this study, we report that Ikaros proteins are degraded by the ubiquitin-proteasome pathway in response to factors produced by murine pancreatic cancer cells. Our results further suggest that an increase in CK2 activity leads to Ikaros' degradation and disrupts its localization to pericentromeric heterochromatin in our murine pancreatic TB model. This loss of Ikaros expression is accompanied by an imbalance in T cell homeostasis. More specifically, we observe a significant decrease in effector CD4+ and CD8+ T cells but an increase in Treg percentages in TB and spontaneous pancreatic cancer models. T-cell specific defects in Ikaros protein expression were also observed in TB CD3+ T cells. Apigenin, a natural plant flavonoid and CK2 inhibitor, restored expression of some Ikaros isoforms in our TB model. Apigenin also displayed immunological benefits evident by enhanced anti-tumor immunity in TB mice. These data provide mechanistic and functional evidence that pharmacological inhibition of CK2 can regulate Ikaros expression and identifies the possible involvement of Ikaros in regulating T cell immune responses in murine pancreatic cancer.
Subjects/Keywords: Transcription Factor; CK2; PP1; Ubiquitination; Apigenin; Cell Biology; Medical Molecular Biology; Medical Sciences
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APA (6th Edition):
Nelson, N. D. (2015). Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer. (Thesis). University of South Florida. Retrieved from https://scholarcommons.usf.edu/etd/5810
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Nelson, Nadine D. “Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer.” 2015. Thesis, University of South Florida. Accessed February 28, 2021.
https://scholarcommons.usf.edu/etd/5810.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Nelson, Nadine D. “Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer.” 2015. Web. 28 Feb 2021.
Vancouver:
Nelson ND. Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer. [Internet] [Thesis]. University of South Florida; 2015. [cited 2021 Feb 28].
Available from: https://scholarcommons.usf.edu/etd/5810.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Nelson ND. Ikaros Deficiency Leads To An Imbalance in Effector and Regulatory T Cell Homeostasis in Murine Pancreatic Cancer. [Thesis]. University of South Florida; 2015. Available from: https://scholarcommons.usf.edu/etd/5810
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Arkansas
25.
Alismail, Hanan Abdulaziz.
Enhanced Pancreatic beta-cells Proliferation and Functionality.
Degree: MS, 2013, University of Arkansas
URL: https://scholarworks.uark.edu/etd/955
► Biologically functional beta-cells proliferate at an extremely low rate with limited turnover capacity. This cellular property hinders cell-based therapy for clinical applications. Many attempts…
(more)
▼ Biologically functional beta-cells proliferate at an extremely low rate with limited turnover capacity. This cellular property hinders
cell-based therapy for clinical applications. Many attempts have been made to develop techniques that allow large quantities of production of clinically relevant islet β-cells in vitro. A line of studies demonstrates that functional beta-cells can proliferate under certain circumstances, providing hope for generating and expanding these cells in vitro and transplanting them into the recipient. In this study, we showed that a membrane substrate offers a better niche for beta
cell proliferation and insulin secretion. Mouse beta cells were grown on a tissue culture plate (TCP) as a control as well as on polyethylene terephthalate (PET) membrane, and
cell numbers were counted four times at 48 hours intervals. The
cell doubling time was shortened from 64.7±0.4 h for beta cells grown on TCP, to 38.6±0.5 h (p-value 0.03) for those grown on PET membrane substrate with a pore size of 1µm. In addition, there was an increase of approximately ten to thirteen fold in insulin gene expression in cells cultured on PET compared to that on TCP (p-value 0.02). Furthermore, to investigate the mechanism of the enhanced proliferation and insulin production using membrane substrate, the expression profile of eighty-four genes that are involved in the apoptotic pathway were measured by quantitative real time polymerase chain reaction (qRT-PCR). Enhancements in Akt and Bcl2 gene expression were detected. These findings demonstrate that a membrane substrate can offer better physicochemical cues for enhancing β-cells proliferation and function in vitro.
Advisors/Committee Members: Sha Jin, Robert Wideman, Dan Lessner.
Subjects/Keywords: Biological sciences; Cells; niche; pancreas; proliferation; Medical Cell Biology; Medical Molecular Biology
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APA (6th Edition):
Alismail, H. A. (2013). Enhanced Pancreatic beta-cells Proliferation and Functionality. (Masters Thesis). University of Arkansas. Retrieved from https://scholarworks.uark.edu/etd/955
Chicago Manual of Style (16th Edition):
Alismail, Hanan Abdulaziz. “Enhanced Pancreatic beta-cells Proliferation and Functionality.” 2013. Masters Thesis, University of Arkansas. Accessed February 28, 2021.
https://scholarworks.uark.edu/etd/955.
MLA Handbook (7th Edition):
Alismail, Hanan Abdulaziz. “Enhanced Pancreatic beta-cells Proliferation and Functionality.” 2013. Web. 28 Feb 2021.
Vancouver:
Alismail HA. Enhanced Pancreatic beta-cells Proliferation and Functionality. [Internet] [Masters thesis]. University of Arkansas; 2013. [cited 2021 Feb 28].
Available from: https://scholarworks.uark.edu/etd/955.
Council of Science Editors:
Alismail HA. Enhanced Pancreatic beta-cells Proliferation and Functionality. [Masters Thesis]. University of Arkansas; 2013. Available from: https://scholarworks.uark.edu/etd/955
University of Pennsylvania
26.
Rieck, Sebastian.
The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α.
Degree: 2011, University of Pennsylvania
URL: https://repository.upenn.edu/edissertations/984
► Diabetes mellitus is an increasingly prevalent metabolic disorder that is estimated to affect over 300 million people by 2025. Common to either type 1 or…
(more)
▼ Diabetes mellitus is an increasingly prevalent metabolic disorder that is estimated to affect over 300 million people by 2025. Common to either type 1 or type 2 diabetes is a progressive inadequacy of functional β-cell mass. Recent studies have shown that during times of prolonged metabolic demand for insulin, the endocrine pancreas can respond by increasing β-cell mass, both by an increase in cell size and by changes in the balance of β-cell proliferation and apoptosis. Advances that further our knowledge of the molecular factors that control both β-cell proliferation and survival will be crucial for understanding the homeostasis of β-cell mass during adulthood, and are pivotal for any attempt to use instructive cues to induce the proliferation of terminally differentiated fully functional insulin-producing β-cells that are suitable for transplantation. However, no systematic study that investigates the expression profile of the islet’s response to pregnancy in vivo, a physiological state of insulin resistance, has been reported thus far.
In the first part of my thesis, I characterized the gene expression signature of pancreatic islets during pregnancy by performing large-scale expression profiling of islets isolated from 4- to 5-month-old non-pregnant and pregnant female mice at day 14.5 of gestation, the peak of β-cell proliferation. I identified a total of 1,907 genes as differentially expressed, and demonstrated the induction of both proliferative and survival pathways in the islet during pregnancy. A comparison of our pregnancy gene set with two additional models of islet expansion suggests that diverse mechanisms can be recruited to expand islet mass. One of the genes that is required for β-cell proliferation during pregnancy in mice is the transcription factor HNF4α.
In an attempt to translate knowledge gained using the pregnancy paradigm, I hypothesized that HNF4α is a human β-cell mitogen. To address this question, in the second part of my thesis, I employed adenoviral-mediated overexpression of a pancreas-specific isoform of HNF4α (HNF4α8) in primary human islets. HNF4α8 stimulated β-cells to enter the cell cycle, and led to a greater than 300-fold increase in the number of β-cells that entered S-phase, without detectable change in glucose stimulated insulin secretion. However, HNF4α8 overexpressing β-cells showed signs of cell cycle arrest, caused by activation of the DNA damage response associated with replication stress, ultimately resulting in a senescence-like phenotype independent of caspase-dependent apoptosis. Overexpression of HNF4α8 together with known β-cell mitogens, also further increased cell cycle entry of β-cells, strengthening the argument that HNF4α8 is a mitogenic signal in the human β-cell. Additionally, I observed a substantial proportion of β-cells stimulated to enter the cell cycle by CDK6 and CYCLIN D3 to also exhibit both markers of cell cycle arrest and double stranded DNA damage. In summary, the DNA damage response is a barrier to efficient human β-cell proliferation in vitro,…
Subjects/Keywords: beta-cell proliferation; diabetes mellitus; regeneration; Endocrinology; Medical Cell Biology; Medical Genetics; Medical Molecular Biology; Medical Physiology; Medical Sciences; Pharmacology; Physiological Processes
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APA ·
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Export
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APA (6th Edition):
Rieck, S. (2011). The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α. (Thesis). University of Pennsylvania. Retrieved from https://repository.upenn.edu/edissertations/984
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Rieck, Sebastian. “The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α.” 2011. Thesis, University of Pennsylvania. Accessed February 28, 2021.
https://repository.upenn.edu/edissertations/984.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Rieck, Sebastian. “The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α.” 2011. Web. 28 Feb 2021.
Vancouver:
Rieck S. The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α. [Internet] [Thesis]. University of Pennsylvania; 2011. [cited 2021 Feb 28].
Available from: https://repository.upenn.edu/edissertations/984.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Rieck S. The Generation of Fully Functional β-Cells by Proliferation: Lessons From Pregnancy and HNF4α. [Thesis]. University of Pennsylvania; 2011. Available from: https://repository.upenn.edu/edissertations/984
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Louisville
27.
Kurlawala, Zimple.
UBQLN1 : a multi-domain protein with multiple functions.
Degree: PhD, 2017, University of Louisville
URL: 10.18297/etd/2754
;
https://ir.library.louisville.edu/etd/2754
► There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL),…
(more)
▼ There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders including Alzheimer’s disease, Amyotropic Lateral Sclerosis and lung cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 can both facilitate degradation (Ataxin3, EPS15) and stabilize (PSEN1/2, BCLb) substrates it binds. The signal that determines this fate is unknown and there is conflicting data to support the existing working model of UBQLN1. BCLb is a member of BCL2 family of proteins that maintain the balance between apoptosis and survival in cells. BCLb is anti-apoptotic and interacts with UBQLN1. Using BCLb as a model substrate, we characterized UBQLN1-substrate interaction. We identified the first two STI domains of UBQLN1 as critical for binding of the UBA domain to these proteins slows their degradation. Similarly, we showed that UBQLN1 interacts with IGF1R and ESYT2 through the STI domains and binding stabilizes these proteins through its UBA domain. Interactions that are not dependent on STI domains, for example UBL mediated interaction with PSMD4 and BAG6, do not appear to be stabilized by UBQLN1. We conclude that fate of substrates that UBQLN1 associates with, is interaction domain specific. We used data derived from UBQLN1-BCLb interactions to model how UBQLN1 regulates IGF1R in lung adenocarcinoma cells. We have identified Ubiquilin1 as a novel interaction partner of IGF1R, IGF2R and Insulin Receptor. We demonstrate here that UBQLN1 regulates expression and activity of IGF receptors. Following loss of UBQLN1 in lung adenocarcinoma cells, there is accelerated loss of IGF1R post stimulation with ligand. Despite decreased levels of total receptors, the ratio of active:total receptors is higher in cells that lack UBQLN1. We tested for differences in synthesis, degradation, trafficking, autocrine ligand production, survival, migration potential and response to chemotherapy in lung adenocarcinoma cells that have loss of UBQLN1. UBQLN1 also regulates ligand stimulated IGF2R, Insulin Receptor (INSR), Epidermal Growth Factor Receptor (EGFR). UBQLN1 deficient cells demonstrate increased survival when serum starved and stimulation of IGF pathway in these cells increased their migratory potential by 3-fold. In conclusion, UBQLN1 is essential for normal regulation of these receptor tyrosine kinases as UBQLN1 negatively regulates total receptor levels.
Advisors/Committee Members: Beverly, Levi, Siskind, Leah, Siskind, Leah, Ceresa, Brian, Clark, Geoff, Roman, Jesse.
Subjects/Keywords: UBQLN; ubiquilin; BCLb; IGF1R; EGFR; ESYT2; Biological Phenomena, Cell Phenomena, and Immunity; Medical Cell Biology; Medical Molecular Biology; Physiological Processes
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APA ·
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CSE |
Export
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Manager
APA (6th Edition):
Kurlawala, Z. (2017). UBQLN1 : a multi-domain protein with multiple functions. (Doctoral Dissertation). University of Louisville. Retrieved from 10.18297/etd/2754 ; https://ir.library.louisville.edu/etd/2754
Chicago Manual of Style (16th Edition):
Kurlawala, Zimple. “UBQLN1 : a multi-domain protein with multiple functions.” 2017. Doctoral Dissertation, University of Louisville. Accessed February 28, 2021.
10.18297/etd/2754 ; https://ir.library.louisville.edu/etd/2754.
MLA Handbook (7th Edition):
Kurlawala, Zimple. “UBQLN1 : a multi-domain protein with multiple functions.” 2017. Web. 28 Feb 2021.
Vancouver:
Kurlawala Z. UBQLN1 : a multi-domain protein with multiple functions. [Internet] [Doctoral dissertation]. University of Louisville; 2017. [cited 2021 Feb 28].
Available from: 10.18297/etd/2754 ; https://ir.library.louisville.edu/etd/2754.
Council of Science Editors:
Kurlawala Z. UBQLN1 : a multi-domain protein with multiple functions. [Doctoral Dissertation]. University of Louisville; 2017. Available from: 10.18297/etd/2754 ; https://ir.library.louisville.edu/etd/2754
McMaster University
28.
Jafari, Reza.
THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS.
Degree: MSc, 2013, McMaster University
URL: http://hdl.handle.net/11375/15284
► Megakaryocyte cultures are a strong tool for the in vitro investigation of platelet production in platelet disorders. Peripheral blood derived hematopoietic progenitor cells (PB-HPCs)…
(more)
▼ Megakaryocyte cultures are a strong tool for the in vitro investigation of platelet production in platelet disorders. Peripheral blood derived hematopoietic progenitor cells (PB-HPCs) are the most accessible source of HPCs with high potential to produce mature megakaryocytes in vitro; however, they are present in low numbers making peripheral blood an inefficient source. Additionally, a megakaryocyte culture with an optimized thrombopoietin (TPO) concentration is required which can reliably allow the investigation of suppressive effects of antibodies/plasma from immune thrombocytopenia (ITP) patients. In this study, we developed a megakaryocyte culture with the utilization of human PB-HPCs in an efficient fashion resulting in the production of high purity megakaryocytes in a TPO-dependent manner. The mononuclear fraction was collected from 180 mL of peripheral whole blood and CD34+ cells were isolated by a positive selection yielding the average of 5.5 x 105 ± 2.5 x 105 CD34+ cells (n = 18). Using 96-well tissue-culture plates and seeding 10,000 CD34+ cells/well, the average of 13 experiments in triplicate can be set up utilizing isolated CD34+ in an efficient manner. Capitalizing on a TPO dose-dependent megakaryocyte production experiment, 20 ng/mL was established as the TPO concentration which resulted in the production of mature megakaryocytes without reaching the plateau in megakaryopoiesis response. On day 11 of culture, the expression of megakaryocytic lineage (CD41/61+) and maturation (CD41/61+CD42+) markers peaked at 90.65% and 76.10%. In conclusion, this culture system has broad application for investigation of platelet disorders and drug discovery which can be accessible to all researchers.
Master of Science (MSc)
Advisors/Committee Members: Nazi, Ishac, Arnold, Donald M., Truant, Ray, Biochemistry and Biomedical Sciences.
Subjects/Keywords: Megakaryocyte culture; megakaryopoiesis; platelets; thrombopoietin; ITP; autoantibody; hematopoietic progenitor cells; peripheral blood; polyploidy; Medical Cell Biology; Medical Cell Biology
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APA ·
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APA (6th Edition):
Jafari, R. (2013). THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/15284
Chicago Manual of Style (16th Edition):
Jafari, Reza. “THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS.” 2013. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/15284.
MLA Handbook (7th Edition):
Jafari, Reza. “THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS.” 2013. Web. 28 Feb 2021.
Vancouver:
Jafari R. THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS. [Internet] [Masters thesis]. McMaster University; 2013. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/15284.
Council of Science Editors:
Jafari R. THE DEVELOPMENT AND OPTIMIZATION OF A HUMAN MEGAKARYOCYTE CULTURE FROM HEMATOPOIETIC PROGENITOR CELLS ISOLATED FROM NORMAL PERIPHERAL BLOOD FOR IN VITRO INVESTIGATION OF PLATELET DISORDERS. [Masters Thesis]. McMaster University; 2013. Available from: http://hdl.handle.net/11375/15284
McMaster University
29.
Sukumar, Aravin.
The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells.
Degree: MSMS, 2011, McMaster University
URL: http://hdl.handle.net/11375/11361
► Glomerulosclerosis (GS) is the irreversible scarring of glomerular tissue which underlies the development of chronic kidney disease (CKD). Increased intraglomerular capillary pressure (Pgc) is…
(more)
▼ Glomerulosclerosis (GS) is the irreversible scarring of glomerular tissue which underlies the development of chronic kidney disease (CKD). Increased intraglomerular capillary pressure (Pgc) is a major contributor to the development of GS and can occur in both hypertensive and diabetic patients. With elevated Pgc, in vitro and in vivo evidence suggest that mesangial cells (MC) experience cyclic stretch and secrete pro-fibrotic factors such as connective tissue growth factor (CTGF) which contributes to GS. The signaling pathways that are activated in response to elevated Pgc and lead to extracellular matrix (ECM) production in MCs are the main focus of this thesis. Previous data demonstrated activation of the Rho GTPase, Rac1, with cyclic stretch in MCs. Furthermore, the most characterized effector of Rac1, p21-activated kinase (PAK), has been observed to have a role in endothelial cells (ECs) exposed to mechanical stress. We thus proposed that the Rac1-PAK signaling pathway is involved in mechanical stress signaling in MCs. Our data demonstrate that Rac1-PAK signaling was activated in response to cyclic stretch and required for stretch-induced CTGF production in MCs. RhoA activation was also regulated by Rac1-PAK signaling, and RhoA/ROCK were observed to mediate CTGF upregulation with stretch. Further investigation on the role of Rac1-PAK signaling and how it regulates CTGF in MCs exposed to stretch, will provide insight into potential therapeutic targets to delay the progression of hypertension-mediated CKD.
Master of Science in Medical Sciences (MSMS)
Advisors/Committee Members: Krepinsky, Joan, Health Sciences.
Subjects/Keywords: mesangial cells; mechanical stress; p21-activated kinase; fibrosis; renal disease; connective tissue growth factor; Medical Cell Biology; Medical Cell Biology
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APA (6th Edition):
Sukumar, A. (2011). The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/11361
Chicago Manual of Style (16th Edition):
Sukumar, Aravin. “The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells.” 2011. Masters Thesis, McMaster University. Accessed February 28, 2021.
http://hdl.handle.net/11375/11361.
MLA Handbook (7th Edition):
Sukumar, Aravin. “The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells.” 2011. Web. 28 Feb 2021.
Vancouver:
Sukumar A. The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells. [Internet] [Masters thesis]. McMaster University; 2011. [cited 2021 Feb 28].
Available from: http://hdl.handle.net/11375/11361.
Council of Science Editors:
Sukumar A. The Role of p21-Activated Kinase in Mechanical Stress-Induced Connective Tissue Growth Factor Upregulation in Mesangial Cells. [Masters Thesis]. McMaster University; 2011. Available from: http://hdl.handle.net/11375/11361
University of Kentucky
30.
Stevens, Payton D.
THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER.
Degree: 2018, University of Kentucky
URL: https://uknowledge.uky.edu/biochem_etds/36
► Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show…
(more)
▼ Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides with a significant increase in cell migration and invasion. Erbin interacts with KSR1 and displaces it from the RAF/MEK/ERK complex to prevent signaling propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promotes tumorigenesis and significantly reduces survival. Tumor organoids derived from Erbin/Apc double knockout mice have increased tumor initiation potential along with increased Wnt target gene expression as seen by qPCR. Collectively, the studies within this dissertation identify Erbin as a negative regulator of EMT and tumor progression by directly suppressing Akt and RAS/RAF signaling in vivo.
Subjects/Keywords: Polarity; EMT; Cell Motility; ERK signaling; Scaffold protein; Tumor Suppressor; Medical Cell Biology; Medical Molecular Biology
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APA (6th Edition):
Stevens, P. D. (2018). THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/biochem_etds/36
Chicago Manual of Style (16th Edition):
Stevens, Payton D. “THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER.” 2018. Doctoral Dissertation, University of Kentucky. Accessed February 28, 2021.
https://uknowledge.uky.edu/biochem_etds/36.
MLA Handbook (7th Edition):
Stevens, Payton D. “THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER.” 2018. Web. 28 Feb 2021.
Vancouver:
Stevens PD. THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER. [Internet] [Doctoral dissertation]. University of Kentucky; 2018. [cited 2021 Feb 28].
Available from: https://uknowledge.uky.edu/biochem_etds/36.
Council of Science Editors:
Stevens PD. THE FUNCTION OF ERBIN, A SCAFFOLD PROTEIN, AS A TUMOR SUPPRESSOR IN COLON CANCER. [Doctoral Dissertation]. University of Kentucky; 2018. Available from: https://uknowledge.uky.edu/biochem_etds/36
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