+publisher:"Penn State University" +contributor:("Kent Eugene Vrana, Committee Member")

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Penn State University

1. Lee, Sangmin. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.

Degree: 2014, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/22522

► Dopamine D1 receptor full agonists have been efficacious in Parkinson’s disease (PD) animal models and PD patients. SKF-83959 is reported to be a functionally selective… (more)

▼ Dopamine D1 receptor full agonists have been efficacious in Parkinson’s disease (PD) animal models and PD patients. SKF-83959 is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase (AC) signaling. The signaling bias of SKF-83959 is commonly accepted and proposed to explain D1-mediated behavioral activity in PD animal models, but there is substantial (although not all unanimous) literature that failed to account for SKF-83959-mediated PLC activation. Thus, we decided to conduct an in-depth pharmacological characterization of SKF-83959. Contrary to common assumptions, SKF-83959 is a partial agonist (not an antagonist) at AC in vitro and ex vivo. In addition, it shows partial agonistic activity for β-arrestin activation. SKF 83959 failed to show D1-mediated PLC signaling in a cellular expression system. We conclude that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral effects can be explained solely by its partial D1 agonism for canonical signaling pathway(s). Current dopamine D1 receptor full agonists have poor pharmacokinetic properties due to their intrinsic catechol moiety, and it is important to determine how novel non-catechol D1 ligands might be designed. To provide a scientific platform for structure-based drug design, we investigated the molecular interactions of the D1 receptor with several ergolines that have significant D1 activity and oral bioavailability, but not a catechol moiety. I focused on the conserved amino acids of the D1 receptor (T3.37, S5.42, S5.43, S5.46, F6.51, and F6.52) that are known to play a critical role in ligand interactions and/or receptor activation. Mutations to alanine (T3.37A, S5.42A, S5.43A, S5.46A, F6.51A, and F6.52A) on the D1 receptor were basically used to examine the role of the conserved amino acids in ligand interactions. A T3.37A mutation greatly decreased the D1 affinity and efficacy of the ergolines. However, a hydrogen bond-conservative T3.37S mutation markedly restored the loss of D1 affinity and efficacy suggesting the possible role of a hydrogen bond provided by T3.37. Unexpectedly, a S5.42A mutation increased the D1 affinity and efficacy for D1-mediated AC activation suggesting that this mutation may induce a favorable D1 receptor conformation for the ergolines. Although a S5.43A mutation failed to decrease the affinity of the ergolines consistently, a S5.46A mutation significantly decreased the affinity of the ergolines but to a small degree. Both the S5.43A and S5.46A mutations showed no significant effects on D1 efficacy of the ergolines. S5.42A/S5.46A and S5.43A/S5.46A double mutations elicited equal or greater effects than those of the single mutations. An F6.51A mutation dramatically decreased the D1 affinity of the ergolines, and an F6.52A mutation showed smaller, but significant decreases than the F6.51A mutation. The F6.51A mutation greatly decreased the ergoline efficacy for AC activation, but an… Advisors/Committee Members: Richard Bernard Mailman, Dissertation Advisor/Co-Advisor, Richard Bernard Mailman, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, John Ellis, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: Dopamine D1 receptor; SKF-83959; funtional selectivity; ergolines; rotigotine; structure-based drug design

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APA (6^th Edition):

Lee, S. (2014). Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/22522

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lee, Sangmin. “Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.” 2014. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/22522.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lee, Sangmin. “Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.” 2014. Web. 03 Mar 2021.

Vancouver:

Lee S. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/22522.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lee S. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/22522

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. Stahl, Jill. Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/19242

► X chromosome inactivation (XCI) silences one X chromosome in females to equalize expression between males and females. Despite the chromosome-wide nature of XCI, ~15% of… (more)

▼ X chromosome inactivation (XCI) silences one X chromosome in females to equalize expression between males and females. Despite the chromosome-wide nature of XCI, ~15% of genes escape inactivation. Escapees are frequently found as clusters, suggesting coordinate regulation. Intriguingly, 10% of genes show variable escape and are expressed from the inactive X (Xi) in a subset of women. Variably expressed loci may contribute to normal trait variation amongst females. The goal of this thesis is to better understand regulation of Xi gene expression by evaluating variable genes in an effort to reveal genetic and epigenetic influences. To evaluate variable Xi expression, I isolated a large number of clonal cell lines from both related and unrelated individuals and scored transcribed polymorphisms to quantitatively measure allele-specific expression. The basis of variability due to cell-to-cell differences was examined by testing Xi gene expression in multiple independent clonal lines, and showed that despite inter-individual variation, intra-individual expression is remarkably stable. Strikingly, Xi levels are inherent to a given X as expression can differ even between maternal and paternal Xi clones derived from a single individual. Nonetheless, these results also exclude trans-acting influences for two genes (HCFC1 and NAA10) as the isogenic lines share an autosomal background. Xi heritability was also assessed. For NAA10, divergent Xi expression of the same X in related females excludes heritability, yet similar analysis of HCFC1 is consistent with cis-acting influences. To assess regional influences associated with coordinate regulation of escape, variable genes from two escape domains were examined. Remarkably, clustered genes show extensive Xi variability, prompting redefinition of these domains as ‘escape-prone.’ Within domains Xi levels correlated for most genes, suggesting coordinate regulation of expression within a cluster. Lastly, epigenetic analysis showed promoter hypomethylation for three variable genes independent of Xi expression level, whereas NAA10 methylation was inversely correlated, suggesting hypomethylation contributes to a poised state for some genes. Such results reveal complex regulation on the Xi, and altogether indicate multiple mechanisms of gene regulation. Given that earlier analysis revealed consistent Xi levels for a given X, we propose that additional epigenetic features are essential during establishment of Xi levels. Advisors/Committee Members: Laura Carrel, Dissertation Advisor/Co-Advisor, Laura Carrel, Committee Chair/Co-Chair, Edward Joseph Gunther, Committee Member, Kristin Ann Eckert, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: X chromosome inactivation; X chromosome; gene expression; DNA methylation

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APA (6^th Edition):

Stahl, J. (2013). Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/19242

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Stahl, Jill. “Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome.” 2013. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/19242.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Stahl, Jill. “Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome.” 2013. Web. 03 Mar 2021.

Vancouver:

Stahl J. Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/19242.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Stahl J. Genetic, Epigenetic and Chromosomal Domain Influences on Gene Expression from the Inactive X Chromosome. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/19242

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Vankirk, Colleen Amanda. Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/19858

► Cognitive impairments with non-neurodegenerative brain aging are associated with synapse loss and diminished synaptic plasticity. The molecular mechanisms underlying synaptic loss and reduced plasticity with… (more)

▼ Cognitive impairments with non-neurodegenerative brain aging are associated with synapse loss and diminished synaptic plasticity. The molecular mechanisms underlying synaptic loss and reduced plasticity with normal brain aging are unknown and identification of these pathways could provide targets for therapeutics to either prevent cognitive decline or slow its progression. The major histocompatibility complex class I (MHCI) processing and presentation pathway was first described in the immune system and serves to detect viral antigens and destroy infected cells. However, it has recently been discovered that MHCI is functionally pleiotropic, and plays important roles in the CNS including participating in activity-dependent structural remodeling processes, synaptic refinement, and synaptic plasticity. Previously, we have demonstrated a significant increase in MHCI processing and presentation pathway transcript expression in hippocampal synapses of aged male rats. Given that MHCI reduces glutamatergic and GABAergic synapse density, and under certain conditions, inhibits synaptic plasticity, aberrant MHCI regulation may be a mechanistic pathway in brain aging. With the recent discovery of these new functions of MHCI in the CNS, there is a paucity of data on the expression, localization, and regulation of the MHCI pathway in the CNS across the lifespan in both males and females. This information is required in order to understand MHCI function in the CNS. These studies sought to 1) characterize regional and cellular expression of MHCI across the CNS, 2) examine DNA promoter methylation as a regulatory mechanism underlying differences in MHCI expression across neural regions, 3) assess DNA promoter methylation as a regulatory mechanism underlying differences in MHCI gene expression across ages and sex, 4) determine changes in MHCI and inflammatory transcript expression with advanced age in both males and females across neural regions, and 5) test acute changes in sex hormones as a potential regulatory mechanism controlling MHCI and inflammatory gene expression. We found that MHCI expression is ubiquitously expressed across neural regions but quantitative expression patterns vary significantly. These differences in expression may be regulated through DNA promoter methylation as methylation levels of two classical MHCI isoforms, H2-D1 and H2-K1, differed between regions and were inversely correlated with expression levels. MHCI expression is apparent primarily in neurons across all areas of the CNS examined with some expression in microglia as well. Additionally, inductions in MHCI expression with advanced age were replicated in both male and female mice, with females demonstrating higher induction in inflammatory transcripts when compared to males, suggesting an influence by sex hormones in the regulation of MHCI and inflammatory factors. DNA promoter methylation does not appear to regulate MHCI transcript expression changes with age. When testing the hypothesis that sex hormones, specifically estrogen,… Advisors/Committee Members: Dr Willard M Freeman, Dissertation Advisor/Co-Advisor, Kent Eugene Vrana, Committee Member, Andras Hajnal, Committee Member, Scot R Kimball, Committee Member, Melvin Lee Billingsley, Committee Member.

Subjects/Keywords: aging; MHCI; brain; neuroinflammation

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APA (6^th Edition):

Vankirk, C. A. (2013). Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/19858

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Vankirk, Colleen Amanda. “Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation.” 2013. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/19858.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Vankirk CA. Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/19858.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Vankirk CA. Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/19858

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. Lieu, Christopher Anson. THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12426

► Parkinson’s disease (PD) is the second most common neurodegenerative disorder that is characterized by cell death of the nigrostriatal pathway and loss of dopamine. Although… (more)

▼ Parkinson’s disease (PD) is the second most common neurodegenerative disorder that is characterized by cell death of the nigrostriatal pathway and loss of dopamine. Although current pharmacological therapies such as levodopa (LD) can significantly ameliorate symptoms in early stages of the disease, patients develop drug-induced motor complications in later stages. One such complication is the emergence of abnormal involuntary movements known as drug-induced dyskinesias (DID), which are disabling and limit effectiveness of anti-PD treatments. Despite significant advances in the field for understanding the mechanisms associated with DID, treatment for DID in PD is largely unsatisfactory for many patients. Advancing our understanding of the pathophysiological basis of DID will allow for better development of novel therapies that reduce or prevent DID. The goals of this dissertation research were: 1) to examine novel experimental therapeutics that do not cause DID in animal models of PD; 2) to examine putative mechanisms through which such therapies exert their effects; 3) to examine the role of interhemispheric pathways in the genesis of DID. In experiment 1, we evaluated if the Ayurvedic medication Mucuna pruriens would reduce DID in the rat and primate models of PD. Our results showed that a water formulation of Mucuna pruriens was highly effective in ameliorating parkinsonian deficits with reduced severity of DID. We also used a novel D1 agonist EFF0311 in both the parkinsonian rat and monkey to show that EFF0311 can significantly decrease parkinsonism and reduce the risk of DID. These two experiments support the use of novel pharmacological agents to mitigate the problem of DID. In experiment 2, we showed that seventeen clinically hemiparkinsonian rhesus monkeys exposed to high doses of LD did not develop DID, and that such monkeys had profound unilateral loss of nigrostriatal neurons (90%). In experiment 3, we explored the putative mechanisms for the resistance of hemiparkinsonian monkeys to DID using single-cell and local field potential electrophysiology in two hemiparkinsonian Rhesus monkeys. We show that chronic intermittent LD did not substantially alter firing rate or patterns in the subthalamic nucleus (a downstream nucleus critically implicated in parkinsonism and in genesis of DID). In experiment 4, we used a variety of tracing techniques (retrograde labeling and optogenetic viral vector systems) to label interhemispheric nigrostriatal connections in normal, partial and completely nigrostriatal lesioned hemiparkinsonian rats. We showed that LD administration to completely lesioned rats (the Ungerstedt model) and severely partial lesioned rats (the Winkler model) caused DID. Histological analysis showed loss of interhemispheric nigrostriatal fibers in these dyskinetic animals. Whereas, the partial striatal lesioned model (Sauer and Oertel model) did not develop DID and retained interhemispheric nigrostriatal fibers. In conclusion, these experiments provide novel insights into the pathophysiological… Advisors/Committee Members: Thyagarajan Subramanian, Dissertation Advisor/Co-Advisor, Thyagarajan Subramanian, Committee Chair/Co-Chair, James Robert Connor, Committee Member, Paul Joseph Eslinger, Committee Member, Kent Eugene Vrana, Committee Member, Kathy Steece Collier, Committee Member.

Subjects/Keywords: basal ganglia; nigrostriatal degeneration; movement disorders; alternative and complementary medicines

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APA (6^th Edition):

Lieu, C. A. (2011). THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12426

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lieu, Christopher Anson. “THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS .” 2011. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/12426.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lieu, Christopher Anson. “THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS .” 2011. Web. 03 Mar 2021.

Vancouver:

Lieu CA. THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/12426.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lieu CA. THE ROLE OF INTERHEMISPHERIC PATHWAYS IN PARKINSON’S DISEASE AND DRUG-INDUCED DYSKINESIAS . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12426

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

5. Linton, Samuel Scott. Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment.

Degree: 2017, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/14352ssl136

► Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadliest form of pancreatic cancer. Although surgical resection can be curative, 80-85% of PDAC patients are… (more)

▼ Pancreatic ductal adenocarcinoma (PDAC) is the most common and deadliest form of pancreatic cancer. Although surgical resection can be curative, 80-85% of PDAC patients are not candidates for surgical resection. Chemotherapy with gemcitabine or 5-FU, although largely ineffective and hampered by dose-limiting toxicities, is the only treatment option for most patients. Nanoparticle-encapsulation of chemotherapeutic agents has been shown to improve drug delivery and reduce off-target effects. Our research team has designed, synthesized, and tested a novel drug nanocarrier, calcium phosphosilicate nanoparticles (CPSNPs). CPSNPs were loaded with FdUMP, the active, phosphorylated metabolite of 5-fluorouracil, or gemcitabine monophosphate, a bioactive analogue of gemcitabine. Drug-loaded CPSNPs were surface-decorated with DNA aptamers which bind to the CCKB receptor. Aptamer-targeted CPSNPs showed enhanced delivery of FdUMP payloads to mice bearing orthotopic pancreatic tumors, as evidenced by a significant reduction in thymidylate synthase, the FdUMP target enzyme. This work demonstrated that aptamer-targeted CPSNPs can selectively deliver active drug to tumors in vivo. Targeted drug delivery has the potential to enhance efficacy of chemotherapeutics and simultaneously reduce toxicity. The PDAC tumor microenvironment (TME) is comprised of multiple cell types, including tumor-associated macrophages (TAMs). Tumor cells, TAMs, and other TME cell types are in constant communication. One way in which cells communicate is through exosomes, the body’s endogenous nanoparticles. Although much is known about exosomal proteins and nucleic acids, including mRNA and miRNA, relatively few studies have addressed the lipid component of exosomes. We compared the lipid composition of exosomes from various PDAC cell lines and from normal pancreatic ductal cells (HPDE). This analysis found that exosomes from AsPC-1, a highly aggressive pancreatic cancer cell line, are enriched in the bioactive lipid arachidonic acid. Functionally, AsPC-1 exosomes fused at a higher rate with THP-1-derived macrophages and polarized macrophages to an immunosuppressive M2 phenotype. AsPC-1 exosomes also significantly enhanced macrophage secretion of pro-tumoral factors including PGE2, VEGF, MCP-1, IL-6, IL-1β, MMP-9, and TNFα. This work details exogenous and endogenous nanoparticle-mediated intercellular communication in the PDAC TME, an enhanced understanding of which will inform the development of next-generation treatments for PDAC patients. Advisors/Committee Members: Gail Lynn Matters, Dissertation Advisor/Co-Advisor, Gail Lynn Matters, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, Oranee Tawatnuntachai, Committee Member, Gary Alan Clawson, Outside Member, Peter J Butler, Outside Member, Mark Kester, Special Member.

Subjects/Keywords: Nanoparticle; Macrophage; Fusion; Exosome; Arachidonic Acid; Pancreatic Cancer

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Linton, S. S. (2017). Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/14352ssl136

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Linton, Samuel Scott. “Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment.” 2017. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/14352ssl136.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Linton, Samuel Scott. “Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment.” 2017. Web. 03 Mar 2021.

Vancouver:

Linton SS. Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment. [Internet] [Thesis]. Penn State University; 2017. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/14352ssl136.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Linton SS. Nanoparticle-Mediated Communication in the Pancreatic Tumor Microenvironment. [Thesis]. Penn State University; 2017. Available from: https://submit-etda.libraries.psu.edu/catalog/14352ssl136

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

6. Petro, Kimberly Anna. ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8197

► Botulinum neurotoxin serotype A (BoNT/A), one of seven serotypes of botulinum neurotoxin, is taken up by neurons of the peripheral nervous system. Within the neurons… (more)

▼ Botulinum neurotoxin serotype A (BoNT/A), one of seven serotypes of botulinum neurotoxin, is taken up by neurons of the peripheral nervous system. Within the neurons it catalyzes cleavage of the synaptosomal-associated protein having a mass of 25kDa, SNAP-25, thereby blocking neurotransmission. BoNT/A has been shown to interact with SV2, as well as gangliosides that are often found in lipid rafts. Lipid rafts are microdomains that can be found on the outer leaflet of the plasma membrane and are enriched in cholesterol and glycosphingolipids. To determine whether lipid rafts were needed for BoNT/A activity, those associated with the plasma membranes of murine N2a neuroblastoma cells were disrupted using either the cyclic oligomer methyl-β-cyclodextrin or the polyene filipin. Disruption of cholesterol containing lipid rafts by either reagent did not prevent the action of BoNT/A on murine neuroblastoma N2a cells, in fact activity was enhanced. While our results indicate that disruption of lipid rafts enhances BoNT/A activity, disruption of clathrin-dependent endocytosis appeared to be inhibitory. In addition to disruption of lipid rafts enhancing BoNT/A activity, it also induced neuritogenesis of N2a cells. Therefore, studies were performed to determine the type of process formation induced by disruption of lipid rafts by either MβCD or filipin. Because ganglioside composition has been shown to change during neuronal differentiation, the question of whether process expression was accompanied by changes in ganglioside content or subcellular distribution was addressed. The results indicate that the processes formed were axonal in nature and their expression was accompanied by changes in both ganglioside content and subcellular localization. Advisors/Committee Members: Cara Lynne Schengrund, Committee Chair/Co-Chair, Sergei A Grigoryev, Committee Member, Gail Lynn Matters, Committee Member, Jong Kak Yun, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: differentiation; gangliosides; botulinum neurotoxin; membrane rafts; lipid rafts

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Petro, K. A. (2008). ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8197

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Petro, Kimberly Anna. “ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/8197.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Petro, Kimberly Anna. “ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS .” 2008. Web. 03 Mar 2021.

Vancouver:

Petro KA. ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/8197.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Petro KA. ROLES OF LIPID RAFTS IN BOTULINUM NEUROTOXIN SEROTYPE A ACTIVITY AND DIFFERENTIATION OF NEUROBLASTOMA CELLS . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8197

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

7. Houck, Kristy Lee. SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8344

► Cardiovascular disease, particularly atherosclerosis, is a major cause of concern as it is the primary cause of death today. Atherosclerosis is an inflammatory disease that… (more)

▼ Cardiovascular disease, particularly atherosclerosis, is a major cause of concern as it is the primary cause of death today. Atherosclerosis is an inflammatory disease that involves lipid accumulation, as well as proliferation and inflammation of vascular smooth muscle cells. Our studies further our understanding of the role of lipid regulation in vascular smooth muscle cells. Diglycerides, phospholipid-derived second messengers, regulate PKC-dependent signaling cascades. There are two distinct species that exist, ester-linked and ether-linked, that determine the physiological outcome of the cell. Our studies demonstrate that ester-linked diacylglycerol promotes PDGF-induced proliferation through activation of PKC epsilon-dependent MAPK/ERK growth signaling. On the other hand, ether-linked diglycerides inhibit mitogenesis through inhibition of PKC epsilon-dependent MAPK/ERK signaling and through inhibition PI3K/AKT signaling. These studies demonstrate two mechanisms, a PKC epsilon-dependent and -independent pathway, by which ether-linked diglycerides inhibit mitogenesis in vascular smooth muscle cells. To further understand the role of vascular smooth muscle cell growth, we examined the sphingolipid enzyme, ceramide kinase, responsible for the conversion of ceramide to ceramide-1-phosphate. Ceramide has been shown to stimulate signaling pathways that lead to growth arrest and/or apoptosis, whereas ceramide-1-phosphate has been shown to stimulate proliferation and inflammation. Our studies demonstrate that vascular smooth muscle cells have a direct involvement in endotoxin-induced inflammation and proliferation that is dependent upon ceramide kinase activation and production of ceramide-1-phosphate. Altered sphingolipid flux may be a contributor to determine a cell’s fate between growth arrest and proliferation. These studies demonstrate a novel mechanism by which sphingolipid flux is shifted from proapoptotic ceramide to promitogenic ceramide-1-phosphate through endotoxin-induced toll-like receptor 4 activation. Collectively, our studies reveal several mechanisms by which bioactive lipids may determine vascular smooth muscle cell flux to either proliferation or cell growth arrest. The ability of ether-linked diglycerides to induce growth arrest, without inducing apoptosis, may be of therapeutic value in stent development for angioplasty. In addition, the ability to regulate ceramide kinase may be an effective therapy through inhibition of C1P-induced inflammation associated with vascular diseases, such as atherosclerosis, as well as other inflammatory diseases, such as diabetes. Advisors/Committee Members: Mark Kester, Committee Chair/Co-Chair, Jong Kak Yun, Committee Member, Melvin Lee Billingsley, Committee Member, Cara Lynne Schengrund, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: toll-like receptor; diglycerides; ceramide-1-phosphate; vascular smooth muscle; signaling cascades; cytokine

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Houck, K. L. (2008). SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8344

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Houck, Kristy Lee. “SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/8344.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Houck, Kristy Lee. “SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS .” 2008. Web. 03 Mar 2021.

Vancouver:

Houck KL. SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/8344.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Houck KL. SPHINGOLIPID AND PHOSPHOLIPID METABOLITES REGULATE THE PHENOTYPE OF VASCULAR SMOOTH MUSCLE CELLS . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8344

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

8. Draper, Jeremiah Michael. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8983

► Many important signaling proteins require the post-translational addition of fatty acid chains for their proper subcellular localization and function. One such modification is the addition… (more)

▼ Many important signaling proteins require the post-translational addition of fatty acid chains for their proper subcellular localization and function. One such modification is the addition of palmitoyl moieties by enzymes known as palmitoyl acyltransferases (PATs). Substrates for PATs include C-terminally farnesylated proteins, such as H- and N-Ras, as well as N-terminally myristoylated proteins, such as multiple Src-related tyrosine kinases. Since many of these proteins are involved in intracellular signaling pathways that drive cellular survival and proliferation, and their activity is predicated on specific subcellular localizations, the enzymes that catalyze their posttranslational modifications are attractive drug targets. However, the primary focus of selective drug development in this arena has been on the process of farnesylation, partly because the farnesyltransferases have been cloned, characterized, and used in screens to develop inhibitors. In contrast, the identification and characterization of human PATs has been hindered by the lack of defined assays to characterize these enzymes, thus preventing the direct validation of the involvement of these enzymes in diseases such as cancer. Current assays to measure palmitoylation activity are functional; however, they employ fractionated cell lysates and are relatively low-throughput. These methods, though useful, are insufficient to directly measure PAT activity in intact cells, which would be useful in the identification of human PATs and studies of the regulation of these enzymes. Thus, we sought to develop quantitative and efficient cellular assays to characterize PAT activity in intact cells. To develop these assays, we used cell-permeable, fluorescently-labeled lipidated peptides that mimic the PAT recognition domains of farnesylated and myristoylated proteins. These PAT substrate mimetics are accumulated by SKOV3 cells in a saturable and time-dependent manner. Although both peptides are rapidly palmitoylated, the SKOV3 cells have a greater capacity to palmitoylate the myristoylated peptide than the farnesylated peptide. Confocal microscopy indicated that the palmitoylated peptides co-localized with Golgi and plasma membrane markers, whereas the corresponding non-palmitoylatable peptides accumulate in the Golgi but did not traffic to the plasma membrane. These results indicate that the lipidated peptides provide useful cellular probes for quantitative and compartmentalization studies of protein palmitoylation in intact cells. Exposure of SKOV3 cells to the peptides did not cause cytotoxicity at any concentration within the maximal 2 hr timeframe of the peptide uptake, palmitoylation, and intracellular localization experiments. However, when exposed to the peptides for 72 hrs cytotoxicity did occur in a palmitoylatable and motif-specific manner. Specifically, the non-palmitoylatable forms of both peptides caused minimal cytotoxicity even at the highest concentrations tested. In contrast, the palmitoylatable forms of both peptides exhibited cytotoxicity of… Advisors/Committee Members: Charles Smith, Dissertation Advisor/Co-Advisor, Charles D Smith, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, Michael Verderame, Committee Member, Jong Kak Yun, Committee Member, Melvin Lee Billingsley, Committee Member.

Subjects/Keywords: localization; transformation; Palmitoyl acyltransferase; drug target

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Draper, J. M. (2008). Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8983

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Draper, Jeremiah Michael. “Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/8983.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Draper, Jeremiah Michael. “Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .” 2008. Web. 03 Mar 2021.

Vancouver:

Draper JM. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/8983.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Draper JM. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8983

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

9. Li, Nan. ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS.

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9752

► Although most genes on one X chromosome in mammalian females are silenced by X chromosome inactivation, some genes “escape” X inactivation and are expressed from… (more)

▼ Although most genes on one X chromosome in mammalian females are silenced by X chromosome inactivation, some genes “escape” X inactivation and are expressed from both active and inactive Xs. How these escape genes are transcribed from a largely inactivated chromosome is not fully understood, but underlying genomic sequences are thought to be involved. We developed a transgene approach to ask whether an escape locus, that includes the mouse Jarid1c gene, is autonomous or is instead influenced by X chromosome location. Two BAC clones carrying Jarid1c and adjacent X-inactivated transcripts were randomly integrated into mouse XX embryonic stem cells. Four lines with single copy, X-linked transgenes were identified and we established that each integrated into regions that are normally X inactivated. As expected for genes that are normally subject to X inactivation, BAC transgene transcripts Tspyl2 and Iqsec2 were X inactivated. However, allelic expression and RNA/DNA FISH indicate that transgenic Jarid1c escapes X inactivation. Therefore, transgenes at four different locations on the X recapitulate endogenous inactive X expression patterns. We conclude that escape from X inactivation is an intrinsic feature of the Jarid1c locus and functionally delimit the Jarid1c escape domain as the 112 kb representing the maximum overlap of the BACs tested. Additionally, although extensive chromatin differences normally distinguish active and inactive loci, unmodified BACs are capable of directing proper inactive X expression patterns. Therefore, these studies establish that primary DNA sequence alone, in a chromosome position-independent manner, is sufficient to determine X chromosome inactivation status. This transgene approach will enable further dissection of key elements of escape domains and allow rigorous testing of specific genomic sequences on inactive X expression. Advisors/Committee Members: Laura Carrel, Dissertation Advisor/Co-Advisor, Laura Carrel, Committee Chair/Co-Chair, Sarah Bronson, Committee Member, Sergei A Grigoryev, Committee Member, Kent Eugene Vrana, Committee Member, Teresa L Wood, Committee Member.

Subjects/Keywords: X chromosome inactivation; epigenetics; transgene; embryonic stem cell

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, N. (2009). ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9752

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Li, Nan. “ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS.” 2009. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/9752.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Li, Nan. “ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS.” 2009. Web. 03 Mar 2021.

Vancouver:

Li N. ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS. [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/9752.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Li N. ESCAPE FROM X CHROMOSOME INACTIVATION IS AN INTRINSIC PROPERTY OF THE MOUSE JARID1C LOCUS. [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9752

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

10. Thomas, Georgia K. A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10457

► Mutations can contribute to the tissue overgrowth, disorganization and cellular atypia characteristic of cancer. This has guided current research in the direction of discovering new… (more)

▼ Mutations can contribute to the tissue overgrowth, disorganization and cellular atypia characteristic of cancer. This has guided current research in the direction of discovering new mutations in genes that govern the transformation of normal human cells into malignant ones. A mutagenesis screen in zebrafish recovered the mutant huli hutu (hht), whose pleiotropic, histological phenotype included the kind of tissue disorganization and nuclear atypia that can be seen with precancers and cancer. Identification of such mutations may contribute to our understanding of cytologic cancer phenotypes, and possibly produce additional models for aspects of human disease, including diseases of the eye and gastrointestinal tract. High resolution recombinant mapping using simple sequence repeat markers, generated five candidate genes: dimt1l, pola2, mier3, mrsp36, and cenph. Morpholino antisense knockdown, transcript analysis, and direct sequencing of complementary and genomic DNA revealed a nonsynonymous substitution in the C-terminal domain of Pola2, the B subunit of DNA polymerase alpha-primase. Immunohistochemical staining with cell proliferation markers BrdU and pH3 and TUNEL analysis suggests defects in proliferation, resulting in tissue-specific apoptosis. Ultrastructural analysis reveals a heterochromatin distribution consistent with cells responding to DNA damage. The multiple-organ phenotype seen with hht inspired a genome-wide analysis of pleiotropic phenotypes observed in a collection of zebrafish insertional mutants. Knowledge of pleiotropic phenotypes caused by single gene deficiencies requires characterization extending beyond single organs. However, the proportion of vertebrate genes that function across tissue boundaries is unknown due to the paucity of sensitive and systematic studies in whole model organisms. To address this combinations of anatomical and histological phenotypes were evaluated in 97 zebrafish insertional mutants with known single gene deficiencies. Eleven mutants exhibited defects in a single organ. Eighty-three had a detectable phenotype in two or more organs, and 72 in three or more. The results suggest that a majority of developmental genes in vertebrates function in multiple tissues, and that phenotypic analyses that cross tissue boundaries are required for more comprehensive understanding of gene function. This type of analysis can be applied across other model systems to make functional annotation of metazoan genes more complete, and may be extended to drug discovery and assessment of environmental toxicity. Advisors/Committee Members: Keith C Cheng, Dissertation Advisor/Co-Advisor, Edward Joseph Gunther, Committee Member, Victor Alan Canfield, Committee Member, Kent Eugene Vrana, Committee Member, Keith C Cheng, Committee Chair/Co-Chair, Sarah Bronson, Committee Member.

Subjects/Keywords: cancer; gene identification; mutagenesis screens; pleiotropy; zebrafish

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Thomas, G. K. (2009). A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10457

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Thomas, Georgia K. “A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES .” 2009. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10457.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Thomas, Georgia K. “A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES .” 2009. Web. 03 Mar 2021.

Vancouver:

Thomas GK. A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10457.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Thomas GK. A MOLECULAR AND SYSTEMS BIOLOGY ANALYSIS OF PLEIOTROPIC VERTEBRATE PHENOTYPES . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/10457

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

11. Maddox, Jacquelyln Renee. Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10107

► Mesenchymal stem cells (MSCs) have generated much interest because of the potential they possess in regenerative medicine. However, the biology of these cells is still… (more)

▼ Mesenchymal stem cells (MSCs) have generated much interest because of the potential they possess in regenerative medicine. However, the biology of these cells is still poorly understood primarily because there are no specific markers available to identify them. Ease of harvest and abundance in tissues like bone marrow and adipose tissue makes the cells attractive for various applications in regenerative medicine. The application of these cells in regenerative medicine will require isolation and identification of the cells from a mixture of other cell types. Numerous surface antigens have been shown to be expressed on MSCs, however, these markers are not specific for MSCs alone. The present studies focused on cells harvested from murine and human adipose tissues and were directed toward assessing the effectiveness of a panel of surface antigens attributed to MSCs for stability in culture, identification of MSCs and application in isolating the cells from other cell types. Adipose derived stem cells (ADSCs) isolated from murine inguinal fat pads were sorted into cell subsets expressing CD73, CD90.2, and CD 105. The sorted and unsorted cells were assessed for in vitro and in vivo differentiation in order to determine the effectiveness of each marker to identify cells with high potential to differentiate toward osteogenic lineage. In vitro data showed that the CD73+ and CD105+ cell subsets displayed greater ability to differentiate toward the osteogenic lineage compared to the CD90.2+ subset. However, when the cell subsets were injected locally into mouse femur, no difference in osteogenic differentiation potential was observed. Therefore, this panel of surface antigens is not useful in identifying and isolating putative ADSCs from a variety of cell types. Human studies focused on assessing the effectiveness of early embryonic stem cell marker: Stage Specific Embryonic Antigen (SSEA-4). This antigen was shown to be expressed by MSCs isolated from bone marrow but its effectiveness in characterizing cells harvested from adipose tissue has not been established. Results showed that ADSCs sorted for SSEA-4 possessed a greater ability to differentiate toward the osteogenic, adipogenic, and neurogenic lineages in vitro. The evaluation of the sorted and unsorted cells also included the ability of cell subsets to heal critical sized defects in the calvarial. Data demonstrated that SSEA-4 Sorted and Unsorted ADSCs were able to regenerate a similar amount of bone in vivo. SSEA-4 Sorted and Unsorted ADSCs expressing BMP-2 demonstrated a similar rate of bone deposition; ADSCs expressing BMP-2 had the potential to regenerate a greater amount of bone than ADSCs which did not express the BMP-2 growth factor. Taken together, data indicate that SSEA-4 enriches for mesenchymal stem cells in vitro, however there is no significant difference between in vivo bone regeneration potential between Unsorted and SSEA-4 Sorted ADSCs. Because the cells are removed from their natural niche, the behavior of the cells in vitro compared to in vivo may be… Advisors/Committee Members: Christopher Niyibizi, Dissertation Advisor/Co-Advisor, Christopher Niyibizi, Committee Chair/Co-Chair, Laura Carrel, Committee Member, Henry Joseph Donahue, Committee Member, Cara Lynne Schengrund, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: bone formation; stem cell marker; mesenchymal stem cell; adipose derived stem cell; SSEA-4; osteogenic

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Maddox, J. R. (2009). Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10107

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Maddox, Jacquelyln Renee. “Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells .” 2009. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10107.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Maddox, Jacquelyln Renee. “Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells .” 2009. Web. 03 Mar 2021.

Vancouver:

Maddox JR. Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10107.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Maddox JR. Evaluation of Putative Cell Surface Markers That Characterize Human and Murine Adipose Derived Stem Cells . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/10107

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

12. Seaton, Kelly Elizabeth. THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10263

► Human Immunodeficiency Virus and consequent Acquired Immune Deficiency Syndrome (AIDS) remain pressing global epidemics. A tremendous need exists for new therapies and treatment paradigms due… (more)

▼ Human Immunodeficiency Virus and consequent Acquired Immune Deficiency Syndrome (AIDS) remain pressing global epidemics. A tremendous need exists for new therapies and treatment paradigms due to viral diversity and the high rate of viral mutation and drug resistance. A major limitation of currently available anti-retroviral agents is that these drugs target viral proteins or viral enzymes, rather than host cell components involved in viral replication and pathogenesis. Targeting viral processes and enzymes leads to a high rate of drug resistance due to the rapid mutation of viral enzymes and lack of a proofreading mechanism during reverse transcription. Novel anti-retroviral treatments focusing on inhibiting host cell processes critical for retroviral replication would provide a more robust treatment strategy, as the virus is unlikely to achieve the significant evolution needed to bypass the lost or diminished host cell function. A key host cell process involved in retroviral replication is the N-myristoylation of HIV-Nef and HIV-Gag. This process involves the transfer of a 14-carbon myristate moiety from myristoyl-Coenzyme A to the N-terminus of substrate proteins through the catalytic activity of the N-myristoyltransferase isozymes (NMT1 and NMT2 in humans). The human NMTs share a sequence homology of approximately 75-77%; however, little is known about the unique substrate specificity or function of the NMTs in normal or disease states. Previous reports in the literature suggest that the NMTs exhibit unique substrate specificity in the context of cancer systems; however, little research has been reported to date in regard to the specificity of the NMTs for viral substrate proteins. Elucidation of the specific NMT responsible for HIV-Gag or HIV-Nef would be a significant step toward development of novel anti-retroviral treatments as myristoylation of these proteins plays a key role in retroviral budding and pathogenesis. Our laboratory examined the roles of the individual NMTs in regard to HIV-Gag and HIV-Nef myristoylation using a variety of biochemical and molecular approaches. Fluorescently labeled peptides corresponding to the N-terminal myristoylation sequence of Gag and Nef were synthesized and myristoylated by recombinant human NMT1 and NMT2. Kinetic analysis revealed that NMT1 and NMT2 have 30- and 130-fold lower KMs for Nef than Gag, respectively. Values for Kcat indicate that once Gag or Nef binds to the enzyme, myristoylation by NMT1 and NMT2 proceeds at comparable rates. Furthermore, the catalytic efficiencies for the processing of Gag by NMT1 and NMT2 were equivalent. In contrast, NMT2 had approximately 5-fold higher catalytic efficiency for the myristoylation of Nef than did NMT1. These experiments were confirmed by using full length recombinant Nef protein, which also indicated a lower KM for Nef myristoylation by NMT2 than by NMT1. We then validated the results of the in vitro kinetic data via siRNA knockdown of the NMTs, followed by confocal microscopy to determine consequent effects on… Advisors/Committee Members: Charles D Smith, Dissertation Advisor/Co-Advisor, Charles D Smith, Committee Chair/Co-Chair, Jong Kak Yun, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, Melvin Lee Billingsley, Committee Member, John Warren Wills, Committee Member.

Subjects/Keywords: human N-myristoyltransferases; myristoylation; HIV

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Seaton, K. E. (2009). THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10263

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Seaton, Kelly Elizabeth. “THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION .” 2009. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10263.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Seaton, Kelly Elizabeth. “THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION .” 2009. Web. 03 Mar 2021.

Vancouver:

Seaton KE. THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10263.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Seaton KE. THE HUMAN N-MYRISTOYLTRANSFERASES AS POTENTIAL PHARMACOTHERAPEUTIC TARGETS IN HIV-1 REPLICATION . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/10263

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

13. Nadaraia-Hoke, Shorena. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10156

► Polyamines are ubiquitous, physiological cations that are essential for a wide range of functions in normal cells, including cell proliferation, differentiation, signal transduction, and apoptosis.… (more)

▼ Polyamines are ubiquitous, physiological cations that are essential for a wide range of functions in normal cells, including cell proliferation, differentiation, signal transduction, and apoptosis. Polyamines interact and stabilize various negatively charged macromolecules such as cellular nucleic acids, alter membrane structure and act as modulators of ion channels. Cells utilize complex metabolic systems and multiple compensatory mechanisms to ensure polyamine homeostasis and, even though their functions at the molecular level are not completely understood, polyamines are critical to cell survival. In mammals, the polyamines, spermidine and spermine, are synthesized by two aminopropyltransferases, spermidine- and spermine-synthases, respectively. Both enzymes utilize decarboxylated S-adenosylmethionine and produce a second product, 5’-methylthioadenosine. Recent structural studies have revealed that the catalytic domains of these enzymes share a common fold. However, potentially, they are regulated in different ways. Spermidine synthase has a gatekeeping loop that is thought to control access to the active site, whereas spermine synthase does not have a gatekeeping loop but contains an additional N-terminal domain that may have a regulatory role. In the presented studies, several biophysical methods were used to begin to understand how these enzymes are regulated. Thermotoga maritima spermidine synthase and human spermine synthase were used as model systems. Specifically, the effect of substrates, products, and inhibitors on spermidine synthase were examined using high-throughput high-resolution deuterium exchange mass spectrometry and isothermal titration calorimetry. In addition, N-terminal deletions of human spermidine synthase and single point variants, which are found in Snyder Robinson Syndrome, were characterized to investigate their effect on the tertiary structure and domain organization. The results of these studies point towards a critical role of oligomerization in each enzyme and suggest the existence of novel regulatory mechanisms controlling their activities in the polyamine biosynthetic pathway. Advisors/Committee Members: Dr Flanagan, Dissertation Advisor/Co-Advisor, John Michael Flanagan Jr., Committee Chair/Co-Chair, Anthony Edward Pegg, Committee Member, Kent Eugene Vrana, Committee Member, Ira Joseph Ropson, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: polyamines; spermidine synthase; spermine synthase; isothermal titration calorimetry; snyder-robinson syndrome

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nadaraia-Hoke, S. (2009). STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10156

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nadaraia-Hoke, Shorena. “STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.” 2009. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10156.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nadaraia-Hoke, Shorena. “STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.” 2009. Web. 03 Mar 2021.

Vancouver:

Nadaraia-Hoke S. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10156.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nadaraia-Hoke S. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/10156

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

14. Ganapathi, Sindura B. REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10448

► HERG (Human ether-a-go-go Related Gene) potassium channel is well established as a regulator of cardiac repolarization. Many drugs were found to block HERG as an… (more)

▼ HERG (Human ether-a-go-go Related Gene) potassium channel is well established as a regulator of cardiac repolarization. Many drugs were found to block HERG as an off target effect inducing unintended cardiac arrhythmias, resulting in their removal from the market. Therefore, HERG block is now being screened for all therapeutics going through drug development. Along with being a regulator of cardiac cycle, recent evidence has shown that HERG plays a role in cell proliferation and cancer progression in multiple tumor cell lines and primary tumor cells, making HERG an attractive target for cancer therapy. However, these multiple roles also present a challenge to find drugs that can block HERG in cancer cells, while not inducing cardiac arrhythmias. This work is focused on two promising anti-neoplastic compounds, 1) R-roscovitine, a cyclin-dependent kinase inhibitor that is in phase II clinical trials as an anticancer drug and 2) a sphingolipid, C6-ceramide, which due its pro-apoptotic effects, has shown promise in animals as a potential anticancer agent. Through a combination of electrophysiology, mathematical modeling, and biochemistry, the present study demonstrates that R-roscovitine, due to its extremely fast kinetics of HERG inhibition and open channel selectivity, can inhibit HERG current without an apparent increase in cardiac arrhythmias. C6-ceramide can also inhibit HERG, but via different mechanisms than R-roscovitine. C6-ceramide has dual effects of i) inhibiting HERG and ii) affecting its gating kinetics. The gating changes involve acceleration of channel opening and closing and a hyperpolarzing shift in the voltage dependence of activation, and these changes are mediated by a movement of the channels into the membrane lipid rafts, which are structured lipid microdomains that co-localize important signaling proteins. While the HERG inhibition presumably contributes to ceramide’s anticancer potency, the combination of gating effects and inhibition may reduce the potential negative effect of C6-ceramide on cardiac rhythm. These two different molecules, acting by two independent mechanisms, provide new perspectives in cancer therapy by demonstrating that HERG channels may be exploited as a target for anti-neoplastic treatment with little or no increase in negative cardiovascular side effects. Also, most high-throughput drug screening techniques utilize HERG inhibition as the criteria for the exclusion of the molecule from further drug development. This study demonstrates that along with HERG current inhibition, changes in gating kinetics also need to be taken into account. Gating changes may be able to offset the effects of HERG inhibition on the cardiac action potential, thereby providing the cancer selectivity. Advisors/Committee Members: Dr Mark Kester, Dissertation Advisor/Co-Advisor, Mark Kester, Committee Chair/Co-Chair, Keith S Elmslie, Committee Chair/Co-Chair, Blaise Peterson, Committee Member, Melvin Lee Billingsley, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: sphingolipids; roscovitine; lipid rafts; patch clamp

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ganapathi, S. B. (2010). REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10448

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ganapathi, Sindura B. “REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY .” 2010. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10448.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ganapathi, Sindura B. “REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY .” 2010. Web. 03 Mar 2021.

Vancouver:

Ganapathi SB. REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10448.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ganapathi SB. REGULATION OF HERG POTASSIUM CHANNELS: IMPLICATIONS OF GATING MODIFICATION FOR CANCER THERAPY . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/10448

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

15. Zamule, Stephanie M. ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS.

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10496

► The liver performs an array of functions vital to life including detoxification, production of serum proteins, maintenance of cholesterol homeostasis, production and clearance of bile… (more)

▼ The liver performs an array of functions vital to life including detoxification, production of serum proteins, maintenance of cholesterol homeostasis, production and clearance of bile components, assembly and inter-conversion of amino acids, synthesis and breakdown of glucose, and processing of fatty acids. Current treatments for liver failure are inadequate, relying on liver or hepatocyte transplantation, both of which are significantly limited by insufficient donor tissue, donor-to-donor variability in tissue quality, and the risk of rejection, infection, or adverse immune response in the recipient. Human embryonic stem cells (hESCs) – derived from the inner cell mass of developing blastocysts and capable of giving rise to any cell type in the body upon exposure to the appropriate conditions – offer promise as an alternative source of cells from which a supply of hepatocytes may be derived for therapeutic transplantations. Hepatocytes derived from hESCs would also potentially provide a repository of cells for pharmacological and toxicological studies which rely on hepatocytes obtained from human donors as models for drug metabolism research and predictors of toxicological responses that may be associated with exposure to xenobiotic compounds. While a number of studies have demonstrated that hESCs are capable of differentiating into hepatic precursors, the precise means by which these cells may be derived, and the genes governing this multifaceted process, have yet to be fully elucidated. In this investigation we employed a unique hepatic differentiation protocol in which hESCs are cultured for only 10 days on collagen matrix in our hepatocyte media (William’s E Media supplemented with HEPES, glutamine, antibiotics, dexamethasone, insulin, transferrin, selenium, and linoleic acid/albumin). The resulting cell population exhibits hepatic-like cell morphology and decreased expression of ‘stemness’ markers including certain transcription factors, surface antigens, and enzymes. The hESC-derived hepatic-like cells express enhanced levels of hepatic markers including transcription factors, nuclear receptors, liver-generated plasma proteins, protease inhibitors, metabolic enzymes, and biotransformation enzymes. Acquisition of hepatic function is confirmed by the cells’ ability to transport anionic compounds and store glycogen. Notably, expression of the constitutive androstane receptor (CAR) – a nuclear receptor which, in the adult liver, is involved in the regulation of diverse physiological processes including all three phases of hepatic biotransformation and elimination as well as energy metabolism and lipid homeostasis – is highly increased in the hepatic-like cells, to levels approaching those of cultures of primary human hepatocytes. CAR is also expressed robustly and consistently in human fetal liver tissue obtained from subjects of a range of gestational ages. Modulation of CAR levels in differentiating hESCs using a lentivirus system – which we demonstrate to stably and robustly transduce both hESCs and cultures… Advisors/Committee Members: Curtis John Omiecinski, Dissertation Advisor/Co-Advisor, Curtis John Omiecinski, Committee Chair/Co-Chair, Gong Chen, Committee Member, Peter John Hudson, Committee Member, Gary H Perdew, Committee Member, John Patrick Vanden Heuvel, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: embryonic stem cells; constitutive androstane receptor; liver; differentiation; nuclear receptor; development; lentivirus

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zamule, S. M. (2010). ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10496

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Zamule, Stephanie M. “ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS.” 2010. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/10496.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Zamule, Stephanie M. “ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS.” 2010. Web. 03 Mar 2021.

Vancouver:

Zamule SM. ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS. [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/10496.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Zamule SM. ROLE OF THE CONSTITUTIVE ANDROSTANE RECEPTOR IN THE DERIVATION OF HEPATIC-LIKE CELLS FROM HUMAN EMBRYONIC STEM CELLS. [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/10496

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

16. Ackermann, Joseph Michael. NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6533

► Ornithine decarboxylase (ODC) is known to have an important role in cell transformation, but that role is not well understood. The scientific and clinical value… (more)

▼ Ornithine decarboxylase (ODC) is known to have an important role in cell transformation, but that role is not well understood. The scientific and clinical value of reducing the activity of ODC, a key enzyme in the biosynthesis of polyamines, is well appreciated. Polyamines are necessary components for cell growth and manipulation of polyamine homeostasis may be an effective strategy for the treatment of a number of disorders, including neoplastic diseases. Indeed, -difluoromethylornithine (DFMO), a specific enzyme-activated irreversible inhibitor of ODC is currently in clinical trials as a potential chemopreventative/therapeutic agent and is clinically used for other disorders. However, the effectiveness of DFMO is limited by the drug's pharmacokinetic profile and the unique regulation of ODC. Targeting ODC mRNA may be an effective method to reduce ODC activity due to the enzyme's extensive regulation at the translational and protein levels. The half-life of ODC is among the shortest of any known protein. Due to the rapid turnover of ODC protein, cells are reliant on translation of new protein to maintain or elevate ODC activity. A number of reports have indicated that little to no change in ODC mRNA content is often detected upon substantial increases or decreases in ODC protein content and activity. Reversible inhibitors of ODC protein have a disadvantage because they can stabilize ODC from degradation. The initial inhibition of ODC leads to increased ODC transcription and active ODC can accumulate in the cells. Conversely, the efficacy of irreversible inhibitors may be limited by the short half-life of ODC. Therefore targeting ODC mRNA, rather than protein, may be a better strategy. An approach to develop an effective 10-23 DNAzyme and hammerhead ribozyme against ODC is described in these studies. DNAzymes and ribozymes bind to a cognate RNA substrate via Watson-Crick base pairing hybridization arms and subsequently catalyze cleavage of a phosphodiester bond of the RNA. The major difference between the two is the base composition; DNAzymes are composed of DNA, ribozymes of RNA. DNAzymes capable of cleaving the target ODC RNA were identified in vitro and further characterized by the effect each had on ODC protein and activity levels using in vitro translated ODC RNA. ODC protein levels and activity correlated well with the RNA cleavage activity of the DNAzyme. A DNAzymes that exhibited good activity was optimized for use in cell culture studies. The length of the DNAzyme hybridization arms was altered and kinetics were performed to identify the most catalytically efficient configuration. One DNAzyme, DZ IV, with equal length arms of nine nucleotides proved to be the most catalytically efficient. In HEK 293 cells, DZ IV was able to reduce the amount of translated ODC protein resulting in ~80% reduction in ODC activity—a statistically significant enhancement over the antisense effect of a catalytically inactive DNAzyme. The effectiveness of DZ IV was evaluated an in vivo model with clinical… Advisors/Committee Members: Anthony Edward Pegg, Committee Chair/Co-Chair, Melvin Lee Billingsley, Committee Member, Mark Kester, Committee Member, Lisa M Shantz, Committee Member, Charles D Smith, Committee Member, Kent Eugene Vrana, Committee Member.

Subjects/Keywords: polyamines; ornithine decarboxylase; gene silencing; DNazyme; ribozyme; antisense oligodeoxynucleotides; difluoromethylornithine; DFMO; resonance energy transfer; RET; FRET; catalytic nuleic acids

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ackermann, J. M. (2008). NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6533

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ackermann, Joseph Michael. “NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION.” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/6533.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ackermann, Joseph Michael. “NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION.” 2008. Web. 03 Mar 2021.

Vancouver:

Ackermann JM. NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/6533.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ackermann JM. NOVEL APPROACHES TO MODULATE ORNITHINE DECARBOXYLASE ACTIVITY AND TO DETERMINE A ROLE FOR ORNITHINE DECARBOXYLASE IN CELL TRANSFORMATION. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6533

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

17. Emmert, Sans Wellington. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8177

► ABSTRACT Levels of dietary selenium are inversely associated with cancer risk in humans, and selenium has played a major role in the field of chemoprevention.… (more)

▼ ABSTRACT Levels of dietary selenium are inversely associated with cancer risk in humans, and selenium has played a major role in the field of chemoprevention. In particular, the organoselenium agents 1,4-phenylenebis(methylene)seleno-cyanate (p-XSC) and its glutathione conjugate, p-XSeSG, are effective in preventing cancers at numerous sites, including the lung in rodent models. In the A/J mouse lung, p-XSC is highly effective in inducing glutathione (GSH), but mechanisms are not well understood. Glutathione is the most abundant antioxidant in animals, and is an important mechanistic factor in chemoprevention. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme responsible for GSH production. Transcriptional regulation of GCL occurs via antioxidant response elements (ARE) in the promoter regions of its genes. Induction of the ARE is in turn regulated by stabilization and nuclear translocation of the transcription factor, Nuclear factor-erythroid 2-Related Factor 2 (Nrf2). Furthermore, the extracellular signal-regulated kinase (ERK) pathway has been shown to play a role in Nrf2 stabilization. Potent chemopreventive phytochemicals, such as sulforaphane (SFN), have been shown to act largely through the Nrf2/ARE pathway. The potential relevance of Nrf2 to GSH induction led to the hypothesis that Nrf2 activation may be involved in organoselenium-mediated induction of GSH, and this was investigated in vivo and in several cell culture models. Here we show that dietary p-XSC induces Nrf2, p-ERK, GCL and GSH in the lung of the Fisher rat, suggesting involvement of Nrf2 and the ERK pathway in GSH induction. In addition, GSH and GCL were induced by p-XSeSG in the Fisher rat. In cell culture studies we observed that p-XSC and p-XSeSG activate an ARE luciferase reporter in an Nrf2-dependent manner. It was also shown that p-XSeSG induced GSH in vitro, and is less toxic than p-XSC. The dependence of GCL induction by p-XSeSG upon Nrf2 was confirmed in wildtype and Nrf2-mutanted Mouse Embryonic Fibroblasts (MEF). These results suggest that p-XSC acts through the Nrf2 pathway in vivo, and that p-XSeSG may be the metabolite responsible for such activation, thus offering p-XSeSG as a less toxic, yet highly efficacious inducer of GSH. Isothiocyanate compounds such as SFN are among the most potent Nrf2 inducers known. We hypothesized that substitution of sulfur with selenium in the isothiocyanate functional group of SFN would result in an isoselenocyanate compound (SFN-isoSe) with enhanced Nrf2 induction capability. Here we show that SFN-isoSe activates an ARE-luciferase reporter in HepG2 cells more potently than SFN. It was also found that SFN-isoSe induces GCL and GSH in MEF cells in an Nrf2-dependent manner. Finally, we provide evidence that SFN-isoSe is more effective in killing HepG2 cancer cells, yet is less toxic to non-cancer MEF cells, than is SFN. These data support our hypothesis, and suggest that SFN-isoSe may be a highly effective chemoprotective agent in vivo. Taken together, these results support the hypothesis that… Advisors/Committee Members: John Peter Richie Jr., Committee Chair/Co-Chair, Karam E El Bayoumy, Committee Member, Thomas E Spratt, Committee Member, Kent Eugene Vrana, Committee Member, Craig Matthew Meyers, Committee Member.

Subjects/Keywords: glutathione; organoselenium; Nrf2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Emmert, S. W. (2008). Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Emmert, Sans Wellington. “Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/8177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Emmert, Sans Wellington. “Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .” 2008. Web. 03 Mar 2021.

Vancouver:

Emmert SW. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/8177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Emmert SW. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations