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Georgia Tech
1.
Saavedra, Gabriela G.
Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA).
Degree: MS, Earth and Atmospheric Sciences, 2019, Georgia Tech
URL: http://hdl.handle.net/1853/63561 
► Multiple studies have found an association between exposure to particulate matter (PM) and adverse health endpoints. One of the suggested mechanisms in which inhalable particles…
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▼ Multiple studies have found an association between exposure to particulate matter (PM) and adverse health endpoints. One of the suggested mechanisms in which inhalable particles exert damage is by inducing the overproduction of reactive oxygen and nitrogen species (ROS/RNS). Hydrogen peroxide is one type of ROS that has been implicated in pathological disorders induced by PM exposure. It has also received increasing attention owing to its dominant role in cellular signaling, metabolic processes, and oxidative stress. However, its biological role upon exposure to PM remains unclear. Secondary organic aerosols (SOA) make up a substantial fraction of ambient fine PM and play a role in the proinflammatory effects of the particles. In this study, the contribution of hydrogen peroxide to intracellular ROS/RNS production upon exposure to water-soluble components of SOA generated from the photooxidation of naphthalene in the presence of NOx (PM samples) was investigated using the general oxidative stress indicator carboxy-H2DCF and catalase as a hydrogen peroxyde scavenger. The intracellular ROS/RNS response with and without the addition of catalase to the PM samples was measured, where the presence of catalase substantially suppressed ROS/RNS response. The hydrogen peroxide produced by water-soluble components in the naphthalene SOA extracted in phosphate buffer solution (PBS) was quantified and ranged from 9.04 ± 0.16 to 11.32 ± 0.27 μM, corresponding to a hydrogen peroxide yield of 3.1 to 3.8 ng/µg. The measured hydrogen peroxide was product of interactions between quinone compounds and peroxide compounds in naphthalene SOA and PBS. Additionally, cells exposed to PM samples released hydrogen peroxide at a rate of 0.21 ± 0.01 to 0.26 ± 0.03 pmol/min/104 cells, which was associated with the mediation of immune responses and/or oxidative stress induced by naphthalene SOA exposure. These findings confirmed that hydrogen peroxide was the main ROS produced by cells exposed to naphthalene SOA and that it was the driver of the PM-induced ROS/RNS response, although this contribution can vary depending on the specific SOA precursors and formation conditions. Findings in this study also showed that, in addition to the hydrogen peroxide produced by cells upon exposure to PM samples, the hydrogen peroxide produced by the PM samples upon interaction with the extracting solution could have diffused into the cell and contribute to the intracellular ROS/RNS response. Although future studies are needed to estimate the contribution of both sources of hydrogen peroxide to the intracellular ROS/RNS response, this study highlights that the diffusion of extracellular ROS/RNS into the cells could represent one of the pathways in which exposure to PM leads to oxidative stress.
Advisors/Committee Members: Ng, Nga Lee (advisor), Weber, Rodney J. (committee member), Champion, Julie A. (committee member).
Subjects/Keywords: Hydrogen peroxide; Naphthalene; Reactive oxygen species; Particulate matter
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APA (6th Edition):
Saavedra, G. G. (2019). Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA). (Masters Thesis). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63561
Chicago Manual of Style (16th Edition):
Saavedra, Gabriela G. “Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA).” 2019. Masters Thesis, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/63561.
MLA Handbook (7th Edition):
Saavedra, Gabriela G. “Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA).” 2019. Web. 03 Mar 2021.
Vancouver:
Saavedra GG. Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA). [Internet] [Masters thesis]. Georgia Tech; 2019. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/63561.
Council of Science Editors:
Saavedra GG. Prominent contribution of hydrogen peroxide to intracellular reactive oxygen species (ROS) generated upon exposure to naphthalene secondary organic aerosols (SOA). [Masters Thesis]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/63561
Georgia Tech
2.
Hyland, Kelly Elise.
Immobilization of adhesive protein domains in PEG hydrogels.
Degree: MS, Materials Science and Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61656
► The fundamental goal of biomaterials design for regenerative medicine is to promote the restoration of functional tissue. In wound healing research, one strategy is to…
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▼ The fundamental goal of biomaterials design for regenerative medicine is to promote the restoration of functional tissue. In wound healing research, one strategy is to introduce space-filling materials, or scaffolds, to intervene and prevent scarring. The scaffold must be nontoxic, permit high rates of oxygen and small molecule diffusion, and offer tissue-matching stiffness. Critically, they must also promote attachment of wound healing cells. A class of materials called synthetic hydrogels meet the first three criteria, but must be functionalized with bioactive ligands to promote cell attachment.
Synthetic hydrogels, most numerously poly(ethylene glycol) (PEG) hydrogels, offer a modular platform for biomaterials design because the bioactive ligand identity and density, as well as hydrogel stiffness, can be precisely and independently controlled. However, PEG hydrogels have seldom been used as a 3D platform for investigating differences in cell behavior when in contact with different extracellular matrix protein domains. Using recombinant protein design, expression, and characterization, this study compares cell behavior when cultured on PEG hydrogels presenting structured protein domains and minimum sequence peptides. We observe differences in cell morphology, protease production and attachment force when cultured on hydrogels with different adhesive protein domains.
Advisors/Committee Members: Champion, Julie A. (advisor), Garcia, Andres J. (committee member), Milam, Valeria (committee member).
Subjects/Keywords: Protein engineering; Hydrogel; Tissue engineering; Wound healing; Regenerative medicine
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APA (6th Edition):
Hyland, K. E. (2018). Immobilization of adhesive protein domains in PEG hydrogels. (Masters Thesis). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61656
Chicago Manual of Style (16th Edition):
Hyland, Kelly Elise. “Immobilization of adhesive protein domains in PEG hydrogels.” 2018. Masters Thesis, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/61656.
MLA Handbook (7th Edition):
Hyland, Kelly Elise. “Immobilization of adhesive protein domains in PEG hydrogels.” 2018. Web. 03 Mar 2021.
Vancouver:
Hyland KE. Immobilization of adhesive protein domains in PEG hydrogels. [Internet] [Masters thesis]. Georgia Tech; 2018. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/61656.
Council of Science Editors:
Hyland KE. Immobilization of adhesive protein domains in PEG hydrogels. [Masters Thesis]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61656
3.
Roberts, Evan Kellett.
Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system.
Degree: MS, Chemical and Biomolecular Engineering, 2017, Georgia Tech
URL: http://hdl.handle.net/1853/58744
► This work presents a structural investigation of two variants of SAF (Self-Assembling Fiber) binary peptides designed by Prof. Derek N. Woolfson and coworkers. SAF refers…
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▼ This work presents a structural investigation of two variants of SAF (Self-Assembling Fiber) binary peptides designed by Prof. Derek N. Woolfson and coworkers. SAF refers to pairs of complementary peptides that assemble into coiled coils upon mixing, which then associate with one another to form fibers. Design features hypothesized to drive co-assembly were evaluated by solid-state nuclear magnetic resonance (NMR) spectroscopy. Our results indicate that the SAF assembly mechanism proposed by Woolfson is partially correct. However, it was also discovered that the α-helical structure formed by the initial co-assembly can undergo conversion to a β-sheet structure, and that this conversion is triggered by rehydration of the dried α-helical nanofibers. To our knowledge, this is the first α-β structural transition ever observed in response to physiologically benign stimuli in a co-assembling de novo binary peptide system.
Advisors/Committee Members: Paravastu, Anant K. (advisor), Grover, Martha A. (advisor), Champion, Julie A. (advisor).
Subjects/Keywords: Peptide co-assembly; Supramolecular structure; Structural dynamics; Solid state NMR; Coiled-coil designer peptides
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APA (6th Edition):
Roberts, E. K. (2017). Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system. (Masters Thesis). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58744
Chicago Manual of Style (16th Edition):
Roberts, Evan Kellett. “Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system.” 2017. Masters Thesis, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/58744.
MLA Handbook (7th Edition):
Roberts, Evan Kellett. “Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system.” 2017. Web. 03 Mar 2021.
Vancouver:
Roberts EK. Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system. [Internet] [Masters thesis]. Georgia Tech; 2017. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/58744.
Council of Science Editors:
Roberts EK. Solid state NMR structural evaluation of the SAF-p1/p2a co-assembling peptide nanofiber system. [Masters Thesis]. Georgia Tech; 2017. Available from: http://hdl.handle.net/1853/58744
Georgia Tech
4.
Baker, Nusaiba F.
Elucidating the spatial and temporal immune response to immunomodulatory materials.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2020, Georgia Tech
URL: http://hdl.handle.net/1853/62765
► Immune modulation therapy has come to the forefront of basic science and clinical research to either interrupt immune dysregulation or induce a specific immune response.…
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▼ Immune modulation therapy has come to the forefront of basic science and clinical research to either interrupt immune dysregulation or induce a specific immune response. This dissertation presents the results of using hydrogel-based biomaterial delivery of therapeutic factors to modulate endogenous mechanisms of innate and adaptive immunity. Our studies integrate pre-clinical mouse models of chronic inflammation and inflammation driven disease states with multi-dimensional flow cytometry analysis to characterize how the local immune cell responses can be manipulated by altering the spatial and temporal presentation of immune modulatory factors. In Aim 1, we designed a synthetic poly(ethylene) glycol (PEG)-based hydrogel to release specialized pro-resolving lipid mediator aspirin triggered resolvin D1 (AT-RvD1) and recombinant human interleukin 10 (IL-10). We hypothesized that an initial quick release of AT-RvD1 after in situ hydrogel gelation would target the myeloid first responders followed by a more gradual release of thiolated IL-10 to influence the activity of cells involved in the later stages of the inflammatory response, mimicking the natural progression of the immune cascade. Here, we utilized a side-by-side internally controlled design wherein bioactive hydrogels were injected adjacent to control hydrogels in the dorsal skinfold window chamber model. We profiled the recruitment of circulating immune cell subsets using flow cytometry, followed by analysis using Spanning-tree Progression Analysis of Density-normalized Events (SPADE), an unbiased clustering algorithm used for dimensionality reduction of high-throughput data. SPADE creates a 2D visualization of complex datasets in a branched “tree” without much needed oversight from the user, which allows for the elucidation of cellular heterogeneity of the immune response, as well as for the identification of rare cell subsets. Aim 1 studies show that the recruitment and re-education of mononuclear phagocytes by dual hydrogel therapy localizes pro-regenerative immune subsets to the hydrogel. The manipulation of innate and adaptive immune phenotypes by IL-10 and AT-RvD1 in the local microenvironment is a promising strategy for enhanced healing in the post-surgical wound. In Aim 2, we utilized alginate and chitosan microparticles to deliver Salmonella AvrA to the site of intestinal inflammation. AvrA is an effector molecule that inhibits activation of pro-inflammatory immune factors. These anti-inflammatory properties make AvrA a promising therapeutic for the amelioration of inflammation. We hypothesized that oral delivery of AvrA microparticles would inhibit the immune response in the gut-associated lymphoid tissue (GALT) but would not lead to a systemic immune suppression. Here, we observed reduced neutrophil infiltration and intracellular TNF expression in the gastrointestinal epithelium. Moreover, SPADE revealed decreased pro-inflammatory T-cell effector markers following AvrA treatment. These data demonstrate the use of biomaterial-based methods to deliver…
Advisors/Committee Members: Botchwey, Edward A. (advisor), Neish, Andrew (advisor), Champion, Julie A. (committee member), Kwong, Gabriel A. (committee member), Gross, Robert E. (committee member).
Subjects/Keywords: Drug delivery; Biomaterials; Pseudotime analysis
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APA (6th Edition):
Baker, N. F. (2020). Elucidating the spatial and temporal immune response to immunomodulatory materials. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/62765
Chicago Manual of Style (16th Edition):
Baker, Nusaiba F. “Elucidating the spatial and temporal immune response to immunomodulatory materials.” 2020. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/62765.
MLA Handbook (7th Edition):
Baker, Nusaiba F. “Elucidating the spatial and temporal immune response to immunomodulatory materials.” 2020. Web. 03 Mar 2021.
Vancouver:
Baker NF. Elucidating the spatial and temporal immune response to immunomodulatory materials. [Internet] [Doctoral dissertation]. Georgia Tech; 2020. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/62765.
Council of Science Editors:
Baker NF. Elucidating the spatial and temporal immune response to immunomodulatory materials. [Doctoral Dissertation]. Georgia Tech; 2020. Available from: http://hdl.handle.net/1853/62765
Georgia Tech
5.
Mukherjee, Abhirup.
Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.
Degree: PhD, Chemical and Biomolecular Engineering, 2019, Georgia Tech
URL: http://hdl.handle.net/1853/63559
► A combined theoretical and computational model was proposed to elucidate the fundamental mechanism of the Wnt/beta-catenin signaling pathway. Analysis suggested that the partial inhibition of…
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▼ A combined theoretical and computational model was proposed to elucidate the fundamental mechanism of the Wnt/beta-catenin signaling pathway. Analysis suggested that the partial inhibition of both beta-catenin phosphorylation and ubiquitination results in an increase in cytosolic concentration of beta-catenin. The inhibition of these post-translational modification steps stems from the partial disassembly of a fraction of the intracellular destruction complexes, and this disassembly is correlated with these destruction complexes relocating to the plasma membrane upon Wnt stimulation. The understanding of the Wnt/beta-catenin pathway was leveraged to design a synthetic dimeric activator of the canonical Wnt signaling pathway, with levels of activation comparable to that of wild-type Wnt-3a. Next, a toolbox of novel optogenetic photoswitches, with tunable dissociation dynamics, was designed by engineering the canonical Wnt protein, LRP6. Finally, transcription-activation based switches were proposed to determine different cell specifications in order to ensure high quality of cardiomyocyte production from human pluripotent stem cells (hPSCs). Taken together, the work discussed in this thesis can serve as a platform for future investigations into several developmental pathways.
Advisors/Committee Members: Kane, Ravi S. (advisor), Garcia, Andres J. (committee member), Champion, Julie A. (committee member), Lu, Hang (committee member), McGrath, Patrick T. (committee member).
Subjects/Keywords: Wnt signaling; Synthetic Wnt agonist; Optogenetics; Transcriptional switches
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APA (6th Edition):
Mukherjee, A. (2019). Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63559
Chicago Manual of Style (16th Edition):
Mukherjee, Abhirup. “Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.” 2019. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/63559.
MLA Handbook (7th Edition):
Mukherjee, Abhirup. “Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway.” 2019. Web. 03 Mar 2021.
Vancouver:
Mukherjee A. Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. [Internet] [Doctoral dissertation]. Georgia Tech; 2019. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/63559.
Council of Science Editors:
Mukherjee A. Designing and developing tools to probe, monitor, and modulate the Wnt signaling pathway. [Doctoral Dissertation]. Georgia Tech; 2019. Available from: http://hdl.handle.net/1853/63559
Georgia Tech
6.
Gray, Warren Dale.
Development of therapeutic systems to treat the infarcted heart.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2014, Georgia Tech
URL: http://hdl.handle.net/1853/53429
► Cardiovascular disease is the leading cause of morbidity and mortality in developed nations, and heart disease is predicted to remain the leading killer for the…
(more)
▼ Cardiovascular disease is the leading cause of morbidity and mortality in developed nations, and heart disease is predicted to remain the leading killer for the foreseeable future. Acute myocardial infarctions—nearly 1.1 million annually occurring in the U.S. alone—are the major cardiovascular disease subgroup. Current treatments for myocardial infarction are limited to interventions that serve to mitigate the initial insult, but clinical applications to protect or regenerate damaged myocardium are lacking. This dissertation examines three therapeutic systems to treat the infarcted heart. First, the decoration of a polymeric nanoparticle with N-acetylglucosamine for the uptake of anti-apoptotic therapeutics to ameliorate cardiomyocyte cell death. Second, novel dendrimeric structure architecture to allow for regioselected decoration of ligands to induce angiogenesis. Third, exosomes secreted from hypoxic cardiac progenitor cells as a naturally derived therapeuticfor angiogenesis and anti-fibrosis, and to provide bio-inspired clues for future therapies.
Advisors/Committee Members: Luo, Ying (advisor), Davis, Michael E. (advisor), Jo, Hanjoong (committee member), Searles, Charles (committee member), Champion, Julie A. (committee member).
Subjects/Keywords: Myocardial infarction; Cardiac protection; Cardiac regeneration; Angiogenesis; Therapeutic system; Nanoparticle; Dendrimer; Exosome; Hypoxia; N-acetylglucosamine
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APA (6th Edition):
Gray, W. D. (2014). Development of therapeutic systems to treat the infarcted heart. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/53429
Chicago Manual of Style (16th Edition):
Gray, Warren Dale. “Development of therapeutic systems to treat the infarcted heart.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/53429.
MLA Handbook (7th Edition):
Gray, Warren Dale. “Development of therapeutic systems to treat the infarcted heart.” 2014. Web. 03 Mar 2021.
Vancouver:
Gray WD. Development of therapeutic systems to treat the infarcted heart. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/53429.
Council of Science Editors:
Gray WD. Development of therapeutic systems to treat the infarcted heart. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/53429
Georgia Tech
7.
Rathan, Swetha.
Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification.
Degree: PhD, Chemical and Biomolecular Engineering, 2016, Georgia Tech
URL: http://hdl.handle.net/1853/58144
► Calcific aortic valve (AV) disease is a strong risk factor for cardiovascular related deaths and is a significant source of mortality worldwide, with the number…
(more)
▼ Calcific aortic valve (AV) disease is a strong risk factor for cardiovascular related deaths and is a significant source of mortality worldwide, with the number of patients requiring AV surgery expected to increase from 250,000 to 850,000 by 2050. However, the molecular mechanisms underlying AV disease have not been well studied or understood. Further, identification of biomarkers that can be used to detect early stage AV disease is also understudied but vital to successfully preventing and/or treating AV disease. It was hypothesized that sclerosis, inflammation and calcification preferentially occurs in the fibrosa compared to the ventricularis due to differential gene expression and oscillatory shear stress. Freshly isolated porcine AV leaflets and an ex vivo shear stress bioreactor was used to test this hypothesis. The low magnitude oscillatory shear stress (OS) appeared to predispose fibrosa to side-dependent calcification via increasing collagen turnover (Col1a1), and thickening of the extracellular matrix (ECM) (fibrosis) and decreasing the expression of genes that protect endothelial function (Klf4 and Enos). The unidirectional pulsatile shear, LS, however, preserved the ECM and gene expression in the ventricularis. The involvement of miRNAs in OS mediated AV pathogenesis was also investigated in a shear- and side-dependent manner. The miR-214 was found to play a role in this OS induced pathogenesis in fibrosa but not ventricularis. Using an ex vivo miRNA silencing protocol, anti-miRNA was delivered to both endothelial and interstitial cells of the AV tissue without compromising the cell viability. Silencing of miR-214 showed that the OS induced pathology in the fibrosa is likely to be mediated via miR-214, klf4 and Tgfβ1 dependent pathway that can lead to AV fibrosis, endothelial-to-mesenchymal transition and eventually sclerosis. The miR-214, however, did not play a role in shear-induced inflammation and calcification. The miR-214, as such, is likely to play a key role in the early onset of side- and shear- dependent AV disease and has a potential to serve as a disease biomarker. Further, an ex vivo AV calcification model was also developed to understand the role of endogenous pro- and anti-calcification factors, such as inorganic pyrophosphate, orthophosphate, and alkaline phosphatase. The functional studies carried out in this dissertation aim to link the mechanosensitive miRNAs to the genes involved in inflammation, endothelial-to-mesenchymal transition, and cell apoptosis etc, which eventually causes AV leaflets to calcify. Thus improved understanding of AV disease mechanisms under different hemodynamic conditions will enable us to improve the design of tissue-engineered valves and develop non-surgical treatment options.
Advisors/Committee Members: Yoganathan, Ajit P. (advisor), Jo, Hanjoong (committee member), Taylor, W. Robert (committee member), Champion, Julie A. (committee member), Nerem, Robert M. (committee member).
Subjects/Keywords: Aortic valve; Hemodynamics; Mechanobiology; MicroRNA; Calcification
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APA (6th Edition):
Rathan, S. (2016). Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58144
Chicago Manual of Style (16th Edition):
Rathan, Swetha. “Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification.” 2016. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/58144.
MLA Handbook (7th Edition):
Rathan, Swetha. “Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification.” 2016. Web. 03 Mar 2021.
Vancouver:
Rathan S. Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/58144.
Council of Science Editors:
Rathan S. Aortic valve mechanobiology- role of altered hemodynamics in mediating aortic valve inflammation and calcification. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/58144
Georgia Tech
8.
Mistilis, Matthew Joseph.
Thermostabilization of influenza vaccine in microneedle patches.
Degree: PhD, Chemical and Biomolecular Engineering, 2016, Georgia Tech
URL: http://hdl.handle.net/1853/58153
► Vaccine delivery to the skin via microneedles confers several advantages over the traditional hypodermic needle and syringe. This work focuses on developing microneedles as a…
(more)
▼ Vaccine delivery to the skin via microneedles confers several advantages over the traditional hypodermic needle and syringe. This work focuses on developing microneedles as a thermostable delivery method for the influenza vaccine that can be completely removed from the cold-chain, thus minimizing cost and wastage during storage and transportation. Microneedle formulations were screened for their effect on influenza vaccine activity during drying. A number of excipients, particularly the combination of arginine and heptagluconate, successfully stabilized influenza vaccine during storage in the dried state and in microneedle patches at ambient or elevated temperatures for up to eighteen months. Influenza vaccine microneedle patches were shown to be resistant against several stresses and remained immunogenic in a mouse model after long-term storage. The primary mechanism of influenza vaccine activity loss during drying was aggregation, which can be mitigated by stabilizing excipients.
Advisors/Committee Members: Prausnitz, Mark R. (advisor), Bommarius, Andreas S. (advisor), Champion, Julie A. (committee member), Compans, Richard W. (committee member), Lieberman, Raquel L. (committee member).
Subjects/Keywords: Vaccine delivery; Vaccine stability; Microneedles; Drug delivery; Formulations; Dermal delivery
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APA (6th Edition):
Mistilis, M. J. (2016). Thermostabilization of influenza vaccine in microneedle patches. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58153
Chicago Manual of Style (16th Edition):
Mistilis, Matthew Joseph. “Thermostabilization of influenza vaccine in microneedle patches.” 2016. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/58153.
MLA Handbook (7th Edition):
Mistilis, Matthew Joseph. “Thermostabilization of influenza vaccine in microneedle patches.” 2016. Web. 03 Mar 2021.
Vancouver:
Mistilis MJ. Thermostabilization of influenza vaccine in microneedle patches. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/58153.
Council of Science Editors:
Mistilis MJ. Thermostabilization of influenza vaccine in microneedle patches. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/58153
Georgia Tech
9.
Srinivasan, Sangeetha.
Conditioning dendritic cell responses using engineered biomaterials for immunotherapy.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2016, Georgia Tech
URL: http://hdl.handle.net/1853/59153
► Pivotal discoveries in the field of immunology over the last five decades have changed the way new therapies are designed for applications as varied as…
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▼ Pivotal discoveries in the field of immunology over the last five decades have changed the way new therapies are designed for applications as varied as organ transplantation, autoimmune diseases or even cancer. In this regard, dendritic cells (DCs) were identified to play an important role in the orchestration of the adaptive immune response. Importantly, the phenotype of DCs is a powerful indicator of their downstream effector functions. In the recent years, parallel advancements made in biomaterial design and biocompatibility considerations are being directly translated into developing improved immunotherapies. Interestingly, biomaterials also elicit differential effects on the host immune response and the phenotypic state of DCs. The first objective of this doctoral thesis was to validate the role of DCs in supporting antigen presentation for a proliferative antigen-specific T cell response in the presence of PLGA, consistent with the previously observed adjuvant effect of PLGA. Herein, by conditionally ablating DCs in a murine CD11c-DTR model, the adjuvant effect of PLGA towards co-delivered OVA was revisited. The diminished proliferation of adoptively transferred OVA-reactive T-cells in these mice was suggestive of mitigated antigen presentation due to the absence of CD11c+ DCs; thereby we demonstrated that the effect of PLGA in vivo on the antigen-specific proliferative T-cell response, a likely early precursor to antibody response, was indeed due to its effects on DC presence and phenotype. The second objective of this thesis was to design, develop and validate a multicomponent, multifunctional immunomodulatory (MI) scaffold comprised of macroporous agarose as the base scaffold material into which were embedded crosslinked gelatin microparticles (MPs), pre-loaded with immunomodulators, for their controlled release to mimic tolerogenic human or murine DC culture conditions. Aided by empirical modeling, using the Weibull equation, of experimental data using ‘model’ proteins, we identified parameters of gelatin MP crosslinking density and number of embedded MPs in agarose to achieve prescribed temporal controlled release of immunomodulators for induction of tolerogenic DCs. The prescribed MI scaffold aimed to release granulocyte monocyte colony-stimulating factor (GM-CSF; delivered within 0-3 days) to induce differentiation of monocyte precursors into DCs after dexamethasone (DEX, delivered within 3-6 days) addition would induce regulatory properties to these cells as well as peptidoglycan (PGN, delivered on days 5-6) to induce an alternative activated phenotype in DCs. Such alternatively activated DCs (aaDCs), are endowed with immunosuppressive as well as directed lymph node migratory properties to effectively exert their tolerogenic effect. Ability of this MI scaffold to induce tolerogenic phenotype in human blood-derived as well as murine bone marrow-derived cells was demonstrated upon in vitro treatment using a large cadre of immunological assessments. In summary, the work in this thesis documents the…
Advisors/Committee Members: Babensee, Julia E. (advisor), Champion, Julie A. (committee member), Thomas, Susan N. (committee member), Botchwey, Edward A. (committee member), Roy, Krishnendu (committee member).
Subjects/Keywords: Biomaterial; Immunotherapy; Dendritic cells; Microparticles; Scaffold; Controlled release; Drug delivery; Autoimmune
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APA (6th Edition):
Srinivasan, S. (2016). Conditioning dendritic cell responses using engineered biomaterials for immunotherapy. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/59153
Chicago Manual of Style (16th Edition):
Srinivasan, Sangeetha. “Conditioning dendritic cell responses using engineered biomaterials for immunotherapy.” 2016. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/59153.
MLA Handbook (7th Edition):
Srinivasan, Sangeetha. “Conditioning dendritic cell responses using engineered biomaterials for immunotherapy.” 2016. Web. 03 Mar 2021.
Vancouver:
Srinivasan S. Conditioning dendritic cell responses using engineered biomaterials for immunotherapy. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/59153.
Council of Science Editors:
Srinivasan S. Conditioning dendritic cell responses using engineered biomaterials for immunotherapy. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/59153
10.
Tuet, Wing-Yin.
Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol.
Degree: PhD, Chemical and Biomolecular Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/59870
► Exposure to atmospheric particulate matter (PM) is a leading global health risk with various proposed mechanisms of action, including the induction of oxidative stress through…
(more)
▼ Exposure to atmospheric particulate matter (PM) is a leading global health risk with various proposed mechanisms of action, including the induction of oxidative stress through PM-initiated production/release of reactive oxygen and nitrogen species (ROS/RNS). This dissertation explores cellular and acellular measurements of PM-induced oxidative stress through systematic laboratory chamber experiments and ambient field studies. A cell-based assay involving murine alveolar macrophages was developed to measure intracellular ROS/RNS produced as a result of aerosol exposure. The area under the dose-response curve was identified as a robust metric to represent ROS/RNS for comparison with different endpoints. A large ambient study with samples collected from urban and rural sites around the greater Atlanta area (n = 104) was conducted using the optimized assay and significant correlations between ROS/RNS and organic constituents were observed for summer samples, highlighting the potential contribution of organic aerosol, particularly summertime photochemically-driven secondary organic aerosol (SOA). To explore these findings, SOA was generated in a series of laboratory experiments from various biogenic (isoprene, α-pinene, β-caryophyllene) and anthropogenic (pentadecane, m-xylene, naphthalene) precursors under different formation conditions (dry vs. humid, NOx, ammonium sulfate vs. iron sulfate seed particles) to probe their effects on PM toxicity. For chemical oxidative potential as measured by dithiothreitol consumption (OP), precursor identity influenced toxicity significantly, with isoprene and naphthalene SOA having the lowest and highest OP, respectively. Both precursor identity and formation conditions influenced ROS/RNS and cytokine (tumor necrosis factor-α and interleukin-6) production. Several response patterns were identified for SOA precursors whose photooxidation products share similar carbon chain length and functionalities. A significant correlation between ROS/RNS levels and aerosol carbon oxidation state was also observed, which may have significant implications as atmospheric aerosol have an atmospheric lifetime of a week, over which oxidation state increases due to photochemical aging, potentially resulting in more toxic aerosol.
Advisors/Committee Members: Ng, Nga L. (advisor), Champion, Julie A. (committee member), Grosberg, Anna (committee member), Lu, Hang (committee member), Weber, Rodney J. (committee member).
Subjects/Keywords: Particulate matter; Oxidative stress
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APA (6th Edition):
Tuet, W. (2018). Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/59870
Chicago Manual of Style (16th Edition):
Tuet, Wing-Yin. “Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol.” 2018. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/59870.
MLA Handbook (7th Edition):
Tuet, Wing-Yin. “Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol.” 2018. Web. 03 Mar 2021.
Vancouver:
Tuet W. Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/59870.
Council of Science Editors:
Tuet W. Cellular and acellular assays for measuring oxidative stress induced by ambient and laboratory-generated aerosol. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/59870
Georgia Tech
11.
Tiernan, Aubrey Rose.
Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells.
Degree: PhD, Chemical and Biomolecular Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/53987
► Cell-based insulin therapies can potentially improve glycemic regulation in insulin dependent diabetes patients and thus help reduce secondary complications. The long-term goal of our work…
(more)
▼ Cell-based insulin therapies can potentially improve glycemic regulation in insulin dependent diabetes patients and thus help reduce secondary complications. The long-term goal of our work is to engineer autologous insulin-secreting intestinal endocrine cells as a non-beta cell approach to alleviate donor cell shortage and immune rejection issues associated with islet transplantation. These cells have been chosen for their endogenous similarity to beta cells, but generating cell constructs with sufficient insulin secretion for therapeutic effect has proven challenging. Previous work in our lab showed that a tissue engineered pancreatic substitute (TEPS) based on an engineered insulin-secreting L cell line, GLUTag-INS, was insufficient in affecting blood glucose levels in streptozotocin-induced diabetic mice, but promising since human insulin was detected in the blood. The objective of this project was therefore to fabricate an improved TEPS based on GLUTag-INS cells and evaluate its suitability as a standalone diabetes therapy. To achieve this objective, the following specific aims were (1) to investigate gene incorporation as a strategy to enhance recombinant insulin secretion from GLUTag-INS cells; (2) to develop and characterize a TEPS in vitro based on a microcapsule system containing improved GLUTag-INS cells with bioluminescence monitoring capability; and (3) to assess therapeutic efficacy of the graft in a diabetic, immune-competent mouse model and use bioluminescence monitoring to elucidate in vivo transplant behavior. This thesis therefore reports on the progression of studies from the genetic and molecular levels for improved insulin secretion per-cell, to the tissue level for enhanced secretion per-graft, and lastly to the preclinical level for therapeutic assessment in a diabetic mouse model.
Advisors/Committee Members: Sambanis, Athanassios (advisor), Koros, William (committee member), Le Doux, Joe (committee member), Thule, Peter M. (committee member), Champion, Julie A. (committee member).
Subjects/Keywords: Diabetes; Bioluminescence; Intestinal L cells; Pancreatic substitute; Cell encapsulation
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APA (6th Edition):
Tiernan, A. R. (2014). Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/53987
Chicago Manual of Style (16th Edition):
Tiernan, Aubrey Rose. “Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/53987.
MLA Handbook (7th Edition):
Tiernan, Aubrey Rose. “Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells.” 2014. Web. 03 Mar 2021.
Vancouver:
Tiernan AR. Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/53987.
Council of Science Editors:
Tiernan AR. Development of a pancreatic substitute based on genetically engineered intestinal endocrine cells. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/53987
Georgia Tech
12.
Sengupta, Aritra.
Intracellular drug delivery using laser activated carbon nanoparticles.
Degree: PhD, Chemical and Biomolecular Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/53996
► We demonstrate intracellular delivery of various molecules by inducing controlled and reversible cell damage through pulsed laser irradiation of carbon black (CB) nanoparticles. We then…
(more)
▼ We demonstrate intracellular delivery of various molecules by inducing controlled and reversible cell damage through pulsed laser irradiation of carbon black (CB) nanoparticles. We then characterized and optimized the system for maximal uptake and minimal loss of viability. At our optimal condition 88% of cells exhibited uptake with almost no loss of viability. In other more intense cases it was shown that cell death could be prevented through addition of poloxamer.
The underlying mechanism of action is also studied and our hypothesis is that the laser heats the CB leading to thermal expansion, vapor formation and/or chemical reaction leading to generation of acoustic waves and then there is energy transduction to the cell causing poration of the cell membrane.
We also delivered anti-EGFR siRNA to ovarian cancer cells. Cells exposed to a laser at 18.75 mJ/cm2 for 7 minutes resulted in a 49% knockdown of EGFR compared to negative control. We established an alternative way to deliver siRNA to knockdown proteins, for the first time using laser CB interaction.
Advisors/Committee Members: Prausnitz, Mark R. (advisor), Thadhani, Naresh N. (committee member), Champion, Julie A. (committee member), Styczynski, Mark P. (committee member), Sambanis, Athanassios (committee member).
Subjects/Keywords: Laser; Nanosecond; Carbon black; Intracellular; Drug delivery; Photoacoustics; Pluronics; Poloxamer; siRNA; EGFR; In-vivo; In-vitro
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APA (6th Edition):
Sengupta, A. (2014). Intracellular drug delivery using laser activated carbon nanoparticles. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/53996
Chicago Manual of Style (16th Edition):
Sengupta, Aritra. “Intracellular drug delivery using laser activated carbon nanoparticles.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/53996.
MLA Handbook (7th Edition):
Sengupta, Aritra. “Intracellular drug delivery using laser activated carbon nanoparticles.” 2014. Web. 03 Mar 2021.
Vancouver:
Sengupta A. Intracellular drug delivery using laser activated carbon nanoparticles. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/53996.
Council of Science Editors:
Sengupta A. Intracellular drug delivery using laser activated carbon nanoparticles. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/53996
Georgia Tech
13.
Liu, Wenying.
Electrospun nanofibers for regenerative medicine.
Degree: PhD, Chemical and Biomolecular Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/54305
► Electrospun nanofibers represent a class of versatile scaffolds for tissue engineering applications owing to their ability to mimic the nanoscale features of the native extracellular…
(more)
▼ Electrospun nanofibers represent a class of versatile scaffolds for tissue engineering applications owing to their ability to mimic the nanoscale features of the native extracellular matrix (ECM). In addition, nanofibers produced by electrospinning can be readily collected as uniaxially aligned assemblies to recapitulate the architecture of the ECM in tissues with anisotropic characteristics, such as tendon-to-bone insertions, tendons, and nerves. This dissertation focuses on the design, fabrication, functionalization, and assessment of various types of scaffolds consisting of aligned nanofibers, which can be used to augment regeneration in tissues with anisotropic structures.
Briefly, for tendon-to-bone insertion repair, I assessed the capability of aligned nanofibers with a gradient in mineral content to induce spatially graded osteogenesis of adipose-derived mesenchymal stem cells (ASCs). I also developed an alternative approach to the production of a gradient in the density of osteoblasts. The graded pattern of osteoblasts generated using both approaches could mimic their distribution in the native tendon-to-bone insertion. To further enhance the stiffness of the scaffolds, a new solution was developed to coat the scaffold with a thicker mineral layer. In a third project, a novel method of generating crimp in aligned nanofibers was developed. A solvent plasticizer was employed to release the residual stress retained in the nanofibers during electrospinning, which led to the generation of crimp. Finally, the outgrowth of neurites derived from embryoid bodies (EBs) was studied using aligned nanofibers as the substrates. Depending on the strength of adhesion between nanofibers and neurites, two patterns of outgrowth – parallel and perpendicular (to the alignment) – were observed. Maturation of neurons derived from dissociated EBs was also investigated, as characterized by their extracellular action potential and the ability to form neuromuscular junctions with co-cultured muscle cells.
Advisors/Committee Members: Xia, Younan (advisor), Behrens, Sven H. (committee member), Champion, Julie A. (committee member), García, Andrés J. (committee member), Taite, Lakeshia J. (committee member).
Subjects/Keywords: Electrospinning; Nanofibers
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APA (6th Edition):
Liu, W. (2014). Electrospun nanofibers for regenerative medicine. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/54305
Chicago Manual of Style (16th Edition):
Liu, Wenying. “Electrospun nanofibers for regenerative medicine.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/54305.
MLA Handbook (7th Edition):
Liu, Wenying. “Electrospun nanofibers for regenerative medicine.” 2014. Web. 03 Mar 2021.
Vancouver:
Liu W. Electrospun nanofibers for regenerative medicine. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/54305.
Council of Science Editors:
Liu W. Electrospun nanofibers for regenerative medicine. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/54305
Georgia Tech
14.
Herrera Estrada, Lina Paola.
Production and Engineering of Therapeutic Protein Nanoparticles.
Degree: PhD, Chemical and Biomolecular Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/56153
► Protein nanoparticles were proposed as therapeutic protein or enzyme delivery vehicles. The production of protein-enzyme nanoparticles via desolvation and self-assembly was investigated and optimized. First,…
(more)
▼ Protein nanoparticles were proposed as therapeutic protein or enzyme delivery vehicles. The production of protein-enzyme nanoparticles via desolvation and self-assembly was investigated and optimized. First, β-galactosidase –a model enzyme– was incorporated into enhanced green fluorescent protein (eGFP) nanoparticles prepared via desolvation. Particle size was shown to be sensitive to type of cross-linker, cross-linking time, and the presence of imidazole. Protein-enzyme nanoparticles are shown to effectively deliver active enzyme to multiple cell lines in vitro. Then the potential of protein nanoparticles for therapeutic protein and enzyme delivery was studied in two diseases models: inflammatory bowel disease (IBD) and breast cancer. Bacterial effector proteins, AvrA and YopJ, were proposed as potential therapeutic agents because of their ability to efficiently subvert the MAPK and NF-κB pathways, which have been implicated in the pathogenesis and progression of IBD and breast cancer. AvrA was incorporated into eGFP nanoparticles and the resulting particles were shown to effectively deliver the effector to target cells in vitro and in vivo, inhibit inflammatory signaling and decrease inflammation in murine colitis models. YopJ was fused to Glutathione-S-Transferase (GST), which caused self-assembly of the fusion into stable nanoparticles. These particles were shown to induce cell death in a panel of breast cancer cell lines, but were not cytotoxic to non-breast cancer cells. Furthermore, these particles decreased cell migration in vitro and performed better or as well as a chemotherapeutic agent, doxorubicin. This data suggests that protein nanoparticles are a biocompatible, high efficiency alternative for intracellular delivery of active enzyme therapeutics, and demonstrates the potential of effector proteins as therapeutic agents.
Advisors/Committee Members: Champion, Julie A (advisor), Kemp, Melissa (committee member), Bommarius, Andreas (committee member), Payne, Christine (committee member), Taite, Lakeisha (committee member).
Subjects/Keywords: Nanoparticles; Enzymes; Bacterial Protein Effectors; Desolvation; Self-assembly; IBD; Breast Cancer; YopJ; AvrA
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APA (6th Edition):
Herrera Estrada, L. P. (2014). Production and Engineering of Therapeutic Protein Nanoparticles. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/56153
Chicago Manual of Style (16th Edition):
Herrera Estrada, Lina Paola. “Production and Engineering of Therapeutic Protein Nanoparticles.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/56153.
MLA Handbook (7th Edition):
Herrera Estrada, Lina Paola. “Production and Engineering of Therapeutic Protein Nanoparticles.” 2014. Web. 03 Mar 2021.
Vancouver:
Herrera Estrada LP. Production and Engineering of Therapeutic Protein Nanoparticles. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/56153.
Council of Science Editors:
Herrera Estrada LP. Production and Engineering of Therapeutic Protein Nanoparticles. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/56153
Georgia Tech
15.
Padmore, Trudy J.
Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages.
Degree: PhD, Chemical and Biomolecular Engineering, 2016, Georgia Tech
URL: http://hdl.handle.net/1853/56336
► Peptide drugs are highly specific and efficacious; interest in them remains high despite the challenges of rapid clearance and degradation. To overcome these limitations peptide…
(more)
▼ Peptide drugs are highly specific and efficacious; interest in them remains high despite the challenges of rapid clearance and degradation. To overcome these limitations peptide delivery systems must prolong release while protecting biological activity. Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion from pancreatic β-cells and is used for treatment of type 2 diabetes. However, GLP-1 undergoes rapid deactivation by proteolytic degradation and its size leads to a short, 2-minute half-life. An affinity-mediated delivery system can prolong half-life, while modification of its amino acid sequence can confer protease resistance. Here we describe a strategy to prolong the release of active Glucagon-like peptide 1 (GLP-1) using Src homology 3 (SH3) domain protein microparticles that bind GLP-1 through affinity-mediated interactions. GLP-1 modified with SH3-binding peptides of weak and strong affinities (GLP-1-SBPs) facilitate tunable release from SH3 microparticles. Release rates of GLP-1 from SH3 microspheres were strongly dependent on the SH3 binding peptide affinity, with the weaker binding GLP-1-SBP13 releasing 40% of its total cargo and the stronger binding GLP-1-SBP2 releasing 20% over a 7-day period. Released GLP-1 stimulated significant increases in Beta cell number, while insulin secretion stimulation was not significant in comparison to basal untreated level. Mathematical models qualitatively replicated affinity-dependent release trends. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages. Asbestos fibers induce chronic lung inflammation and have been associated (WHO estimate) with 105 lung cancer deaths per year worldwide. In the lung, immune cells (macrophages) attempt to engulf inhaled foreign materials (like asbestos), secreting inflammatory molecules. The inability of macrophages to effectively remove asbestos leads to chronic inflammation and disease. Although the health effects of asbestos have been extensively investigated, this study examines the role of fiber length on phagocytosis and molecular inflammatory responses so as to characterize fiber toxicity at the cellular level. A major challenge is obtaining fibers of the same diameter, d, but differing in length, L. Glass fibers, with d ~1micron, were used as a model for asbestos. Samples with different measured length distributions were prepared: aggressive crushing for short fibers populations and successive sedimentation for long fibers populations. The interactions of MH-S murine alveolar macrophages with the fibers were analyzed by time-lapse video microscopy, to qualitatively describe attempted phagocytosis in real time, and by flow cytometry, to quantitatively measure attachment and internalization of fibers. Short fibers were observed to bind to macrophages, being internalized with little effort. Conversely, macrophages literally wrestled with long fibers over many hours, usually with unsuccessful internalization. Short fibers were twice as likely to be internalized as the long…
Advisors/Committee Members: Champion, Julie A. (advisor), Behrens, Sven (committee member), Bommarius, Andreas (committee member), García, Andrés J. (committee member), McDevitt, Todd (committee member).
Subjects/Keywords: GLP-1; Controlled release; Affinity-based release; Protein microspheres; Fiber length; Length models
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Export
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APA (6th Edition):
Padmore, T. J. (2016). Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/56336
Chicago Manual of Style (16th Edition):
Padmore, Trudy J. “Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages.” 2016. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/56336.
MLA Handbook (7th Edition):
Padmore, Trudy J. “Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages.” 2016. Web. 03 Mar 2021.
Vancouver:
Padmore TJ. Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/56336.
Council of Science Editors:
Padmore TJ. Controlled release of GLP-1 from affinity-based protein microspheres and quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by macrophages. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/56336
Georgia Tech
16.
Park, Won Min.
Self-assembly of protein-based suprastructures.
Degree: PhD, Chemical and Biomolecular Engineering, 2015, Georgia Tech
URL: http://hdl.handle.net/1853/58135
► Strategies for self-assembly of protein-based suprastructures were developed. Recombinant protein building blocks were designed, produced, and self-assembled into various suprastructures, which include spheres, vesicles, nanosheets…
(more)
▼ Strategies for self-assembly of protein-based suprastructures were developed. Recombinant protein building blocks were designed, produced, and self-assembled into various suprastructures, which include spheres, vesicles, nanosheets and porous particles. Morphology was manipulated by engineering protein building blocks, controlling self-assembly processes, and combining inorganic nanocrystals into hybrid materials. Self-assembly of spherical protein coacervates was achieved in the extracellular matrix, mediated by spontaneous diffusion-coacervation and high-affinity binding of building blocks. Vesicles and two-dimensional nanosheets were self-assembled from recombinant protein complexes, whose molecular geometry dictated the morphologies of self-assembled structures. Self-clustering hybrid flower-shaped nanoparticles were prepared and further assembled into hierarchically structured porous supraparticles. All the suprastructures were created as modular systems which enabled incorporation folded functional proteins. Enzymes incorporated in the porous supraparticles showed enhanced inactivation of a pro-inflammatory cytokine, tumor necrosis factor-α. The modular design approach, combined with manipulation of morphology, offer opportunities for practical applications.
Advisors/Committee Members: Champion, Julie A. (advisor), Babensee, Julia E. (committee member), Behrens, Sven H. (committee member), Bommarius, Andreas S. (committee member), Sambanis, Athanassios (committee member).
Subjects/Keywords: Protein; Self-assembly
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APA (6th Edition):
Park, W. M. (2015). Self-assembly of protein-based suprastructures. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58135
Chicago Manual of Style (16th Edition):
Park, Won Min. “Self-assembly of protein-based suprastructures.” 2015. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/58135.
MLA Handbook (7th Edition):
Park, Won Min. “Self-assembly of protein-based suprastructures.” 2015. Web. 03 Mar 2021.
Vancouver:
Park WM. Self-assembly of protein-based suprastructures. [Internet] [Doctoral dissertation]. Georgia Tech; 2015. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/58135.
Council of Science Editors:
Park WM. Self-assembly of protein-based suprastructures. [Doctoral Dissertation]. Georgia Tech; 2015. Available from: http://hdl.handle.net/1853/58135
Georgia Tech
17.
Ling, Kevin.
Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease.
Degree: PhD, Chemical and Biomolecular Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61140
► The work presented in this thesis focuses on reengineering naturally-derived, evolutionarily optimized molecules as drug delivery vehicles and therapeutics. We have identified AvrA, used by…
(more)
▼ The work presented in this thesis focuses on reengineering naturally-derived, evolutionarily optimized molecules as drug delivery vehicles and therapeutics. We have identified AvrA, used by Salmonella, as an effector enzyme with therapeutic potential due to its ability to modulate key intracellular signaling pathways in eukaryotic cells and confer anti-inflammatory and anti-apoptotic effects. Chronic inflammation in autoimmune diseases, such as inflammatory bowel disease, is a prime target that could benefit from treatment with AvrA. Modulating intracellular components with the use of enzymes presents a new strategy to combat inflammatory bowel disease. Salmonella possesses a type three needle-like secretion system used to deliver AvrA which can penetrate the cell membrane, giving direct access to the cytosol. Utilizing AvrA absent of Salmonella requires an alternative delivery system. To address this challenge, we engineered a protein nanoparticle encapsulating AvrA capable of intracellular delivery. AvrA nanoparticles were characterized and evaluated for their potential to treat inflammatory bowel disease and a pH responsive oral delivery vehicle made from naturally derived polysaccharides, alginate and chitosan, was used to encapsulate AvrA nanoparticles to increases it clinical potential. We also studied the role of carrier proteins in influencing protein nanoparticle properties. These properties can influence the protein corona that around them when administrated in vivo and guide cellular interactions to maximize cytosolic delivery.
Advisors/Committee Members: Champion, Julie A. (advisor), Kane, Ravi (committee member), Neish, Andrew (committee member), Payne, Christine (committee member), Prausnitz, Mark (committee member).
Subjects/Keywords: AvrA; Nanoparticles; Intracellular delivery; Protein delivery; Oral delivery; Alginate; Chitosan; Microparticles; Protein corona
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APA (6th Edition):
Ling, K. (2018). Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61140
Chicago Manual of Style (16th Edition):
Ling, Kevin. “Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease.” 2018. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/61140.
MLA Handbook (7th Edition):
Ling, Kevin. “Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease.” 2018. Web. 03 Mar 2021.
Vancouver:
Ling K. Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/61140.
Council of Science Editors:
Ling K. Engineering therapeutic AvrA nanoparticles with enhanced uptake and intracellular delivery with applications in inflammatory bowel disease. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61140
18.
Hsieh, Ming-Chien.
Kinetic and structural evolution of functional peptide assembling networks.
Degree: PhD, Chemical and Biomolecular Engineering, 2017, Georgia Tech
URL: http://hdl.handle.net/1853/58708
► The peptide assembly mechanism is important for the development of both functional biomaterials and clinical therapies. Although the assembly structures and assembling pathways have been…
(more)
▼ The peptide assembly mechanism is important for the development of both functional biomaterials and clinical therapies. Although the assembly structures and assembling pathways have been studied for decades, the complex multistep mechanism remains to be clarified. The main goal of this thesis is to investigate the assembly mechanism of functional peptide assemblies. First, the crucial building blocks capable of assembly are synthesized and selected via the dynamic combinatorial networks (DCNs), which yield sequence-defined oligomers with high fidelity. Both experimental analyses and mathematical modeling are applied to confirm the interplay between the chemical distribution and emergent physical transitions in the networks; model discrimination shows that the chemical nature of the DCNs is affected and shifted at different physical stages. Next, to simulate the two-step nucleation process observed in the DCNs, a peptide assembly model is developed with two-step nucleation. The model simulates the phase transitions between different physical phases, and the potential of this model is tested with experimental results from the peptide, Ac-KLVFFAE-NH2. The model is then extended for a polydisperse system, where the peptides undergo oligomerization, to simulate the chemical and physical transitions in the DCNs. The polydisperse model shows that the physical and chemical distribution may reach the steady state independently. The assembly pathway with two-step nucleation is further experimentally investigated with the pH sensitive Abeta(16-22) peptide, which assembles into fiber at neutral pH but tubes at acidic pH. The difference between the nucleation and propagation environments for the two-step nucleation mechanism affects the assembly kinetics and morphological selection. Although Abeta(16-22) assembles into ribbons pH-independently, the ribbon intermediates undergo pH-dependent reaction pathway and transition into different morphologies under different pH conditions. Finally, the catalytic peptide assemblies are analyzed. The methodol substrate is cleaved by Ac-KLVFFAL-NH2 and Ac-OrnLVFFAL-NH2 nanotubes enantioselectively. The experimental results are analyzed with a modified Michaelis-Menten mechanism to resolve the nature of this catalytic system, including the number of peptides per binding site, the enantioselectivity, and the stability of the tubes. The simulations suggest similar binding pocket size for both nanotubes, and the assemblies are stable throughout the entire reaction time. The enantioselectivity for the R- and S-methodol substrate may come from the chemical selectivity of the peptide nanotubes, but not from the difference of the binding affinity, based on the analysis.
The results from this thesis provide a comprehensive investigation of the construction of functional peptide assemblies. The building block synthesis and selection, the assembly structure and mechanism, and the functional properties of the peptide assemblies are reported and discussed, which may provide a broad insight about…
Advisors/Committee Members: Grover, Martha A. (advisor), Lynn, David G. (advisor), Champion, Julie A. (advisor), Ludovice, Peter J. (advisor), Hud, Nicholas V. (advisor).
Subjects/Keywords: Peptide assembly; Kinetics; Catalysis; System chemistry
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APA (6th Edition):
Hsieh, M. (2017). Kinetic and structural evolution of functional peptide assembling networks. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/58708
Chicago Manual of Style (16th Edition):
Hsieh, Ming-Chien. “Kinetic and structural evolution of functional peptide assembling networks.” 2017. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/58708.
MLA Handbook (7th Edition):
Hsieh, Ming-Chien. “Kinetic and structural evolution of functional peptide assembling networks.” 2017. Web. 03 Mar 2021.
Vancouver:
Hsieh M. Kinetic and structural evolution of functional peptide assembling networks. [Internet] [Doctoral dissertation]. Georgia Tech; 2017. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/58708.
Council of Science Editors:
Hsieh M. Kinetic and structural evolution of functional peptide assembling networks. [Doctoral Dissertation]. Georgia Tech; 2017. Available from: http://hdl.handle.net/1853/58708
Georgia Tech
19.
Paunovska, Kalina.
An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.
Degree: PhD, Biomedical Engineering (Joint GT/Emory Department), 2020, Georgia Tech
URL: http://hdl.handle.net/1853/63571
► Lipid nanoparticle (LNP)-mediated nucleic acid delivery can regulate the expression of any gene, making it a promising way to treat disease. However, clinically relevant delivery…
(more)
▼ Lipid nanoparticle (LNP)-mediated nucleic acid delivery can regulate the expression of any gene, making it a promising way to treat disease. However, clinically relevant delivery of RNA therapeutics to non-hepatocytes in vivo remains challenging. Most LNPs are created by mixing an ionizable lipid with PEG, a phospholipid, and cholesterol, allowing the possibility for thousands of chemically distinct LNPs. These nanoparticles are typically screened in vitro in easily expandable cell lines, yet these cell culture conditions are not representative of in vivo tissue microenvironments. LNPs that deliver their payload (e.g. DNA, RNA) successfully in vitro are then validated in vivo. However, because LNPs that tend to work in vitro do not necessarily work in vivo, this often leads to a small number of viable candidates. The objective of this thesis is to use high-throughput DNA barcoding to ask fundamental questions about in vivo drug delivery. In particular, this work presents four significant contributions to the field of nucleic acid delivery. First, this work explores in vitro and in vivo LNP delivery in many cell types (e.g. endothelial, macrophage) from many tissues (e.g. heart, lung, bone marrow) and reveals that in vitro LNP delivery is not predictive of in vivo delivery. Second, cholesterol structure – a previously unperturbed LNP component – is found to impact LNP delivery in vivo. Cholesterol variants are naturally trafficked in lipoproteins (e.g. LDL, VLDL) suggesting that LNP targeting can be tuned by using naturally- or synthetically-derived cholesterol variants. Third, LNPs that deliver RNA to non-hepatocytes more efficiently than to hepatocytes are identified. Fourth, manipulating cell metabolism through exogenous administration of a small molecule is found to impact LNP-delivered mRNA translation in vivo. Finally, the potential for related works and new directions worthy of pursuit within the field nucleic acid drug delivery are discussed. Taken together, this work enables understanding and optimization of the factors that influence non-hepatocyte RNA delivery in vivo.
Advisors/Committee Members: Dahlman, James E. (advisor), Garcia, Andres J. (committee member), Santangelo, Philip J. (committee member), Champion, Julie A. (committee member), Botchwey, Edward A. (committee member).
Subjects/Keywords: Lipid nanoparticles; DNA barcoding; Nucleic acid delivery; RNA therapeutics; Gene therapy
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APA (6th Edition):
Paunovska, K. (2020). An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/63571
Chicago Manual of Style (16th Edition):
Paunovska, Kalina. “An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.” 2020. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/63571.
MLA Handbook (7th Edition):
Paunovska, Kalina. “An investigation of parameters that influence non-hepatocyte RNA delivery in vivo.” 2020. Web. 03 Mar 2021.
Vancouver:
Paunovska K. An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. [Internet] [Doctoral dissertation]. Georgia Tech; 2020. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/63571.
Council of Science Editors:
Paunovska K. An investigation of parameters that influence non-hepatocyte RNA delivery in vivo. [Doctoral Dissertation]. Georgia Tech; 2020. Available from: http://hdl.handle.net/1853/63571
20.
Smith, McKenzie L.
Systematic investigation of protein-metabolite regulatory interactions: methodologies and context.
Degree: PhD, Chemical and Biomolecular Engineering, 2016, Georgia Tech
URL: http://hdl.handle.net/1853/56353
► A systems-level understanding of metabolism will have far-reaching benefits from medicine to ecology to industry, as it will facilitate the comprehensive profiling and prediction of…
(more)
▼ A systems-level understanding of metabolism will have far-reaching benefits from medicine to ecology to industry, as it will facilitate the comprehensive profiling and prediction of metabolic states in organisms of interest. Systematic characterization strategies have thus far been successfully applied at the genomic, transcriptomic, and proteomic levels, but downstream regulatory interactions have remained comparatively underexplored. We believe this is largely due to the wide sensitivity spectrum required to effect a similarly comprehensive study: the binding affinities of known protein-metabolite regulatory pairs span multiple orders of magnitude. The overarching aim of this work was therefore to explore and develop multiple complementary strategies for discovery and characterization of these interactions. An in vitro reaction assay-based pipeline was developed to provide a flexible framework for both the validation of putative regulatory interactions found via other methods, and the discovery of new regulatory interactions over a wide range of binding affinities. Small-molecule microarrays were explored as a potential platform for high-throughput discovery of the stronger range of binding interactions, which work will provide a basis for future development and wide-range implementation of the assay. Additionally, a concurrent metabolomics study of inappetence in spawning salmon yielded insights into the metabolic profile of inappetent versus fed cohorts; these results also provide high-level context for protein- and pathway- level studies. Taken together, these findings provide a methodological framework to increase the efficiency and range of study for protein-metabolite regulatory interactions, as well as lay groundwork for further expansion of that range, ultimately in service of the future development of systems-level metabolic models.
Advisors/Committee Members: Styczynski, Mark P (advisor), Bommarius, Andreas S (committee member), Champion, Julie A (committee member), Fernandez, Facundo M (committee member), Kelly, Wendy L (committee member).
Subjects/Keywords: Allostery; Metabolomics; Systems biology
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APA ·
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APA (6th Edition):
Smith, M. L. (2016). Systematic investigation of protein-metabolite regulatory interactions: methodologies and context. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/56353
Chicago Manual of Style (16th Edition):
Smith, McKenzie L. “Systematic investigation of protein-metabolite regulatory interactions: methodologies and context.” 2016. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/56353.
MLA Handbook (7th Edition):
Smith, McKenzie L. “Systematic investigation of protein-metabolite regulatory interactions: methodologies and context.” 2016. Web. 03 Mar 2021.
Vancouver:
Smith ML. Systematic investigation of protein-metabolite regulatory interactions: methodologies and context. [Internet] [Doctoral dissertation]. Georgia Tech; 2016. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/56353.
Council of Science Editors:
Smith ML. Systematic investigation of protein-metabolite regulatory interactions: methodologies and context. [Doctoral Dissertation]. Georgia Tech; 2016. Available from: http://hdl.handle.net/1853/56353
21.
Chang, Kai.
Structural modification of poly(n-isopropylacrylamide) for drug delivery applications.
Degree: PhD, Chemical and Biomolecular Engineering, 2013, Georgia Tech
URL: http://hdl.handle.net/1853/48947
► Polymeric biomaterials have become ubiquitous in modern medical devices. ‘Smart’ materials, materials that respond to external stimuli, have been of particular interest for biomedical applications…
(more)
▼ Polymeric biomaterials have become ubiquitous in modern medical devices. ‘Smart’ materials, materials that respond to external stimuli, have been of particular interest for biomedical applications such as drug delivery. Poly(n-isopropylacrylamide) (pNIPAAm) is the best studied thermally responsive, biocompatible, ‘smart’ polymer and has been integrated into many potential drug delivery devices; however, the architectural design of the polymer in these devices is often overlooked. My research focus was the exploration of pNIPAAm architecture for biological applications. Two new biomaterials were synthesized as a result.
Architectural modification of linear pNIPAAm was used to synthesize a well-defined homopolymer pNIPAAm with a sharp transition slightly above normal body temperature under isotonic conditions. This polymer required a combination of polymerization and control techniques including controlled radical polymerization, hydrogen bond induced tacticity, and end-group manipulation. The synthesis of this polymer opened up a variety of biomedical possibilities, one of which is the use of these polymers in a novel hydrogel system. Through the use of the controlled linear pNIPAAm synthesized through chain architectural modification, hydrogels with physiological transition temperatures were also synthesized. These hydrogels showed greater shrinking properties than traditional hydrogels synthesized in the same manner and showed physiological mechanical properties.
Highly branched pNIPAAm was also optimized for biological applications. In this case, the branching reduced the efficacy of end-groups in transition temperature modification but increased the efficacy of certain copolymers. The resulting biomaterial was incorporated into a nanoparticle drug delivery system. By combining gold nanoparticles with highly branched pNIPAAm, which was designed to entrap small molecule drugs, a hybrid system was synthesized where heating of the nanoparticle through surface plasmon resonance can trigger drug release from the pNIPAAm. This system proved to be easy to synthesize, effective in loading, and controlled in release.
As shown from the applications, architectural control of pNIPAAm can open up new possibilities with this polymer for biomedical applications. Small structural changes can lead to significant changes in the bulk properties of the polymer and should be considered in future pNIPAAm based medical devices.
Advisors/Committee Members: Taite, Lakeshia J. (advisor), Prausnitz, Mark (committee member), Bommarius, Andreas (committee member), Champion, Julie A. (committee member), Milam, Valeria T. (committee member).
Subjects/Keywords: Polymer architecture; Thermally responsive; Polymeric drug delivery vehicle; Acrylamide; Polymeric drug delivery systems
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APA (6th Edition):
Chang, K. (2013). Structural modification of poly(n-isopropylacrylamide) for drug delivery applications. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/48947
Chicago Manual of Style (16th Edition):
Chang, Kai. “Structural modification of poly(n-isopropylacrylamide) for drug delivery applications.” 2013. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/48947.
MLA Handbook (7th Edition):
Chang, Kai. “Structural modification of poly(n-isopropylacrylamide) for drug delivery applications.” 2013. Web. 03 Mar 2021.
Vancouver:
Chang K. Structural modification of poly(n-isopropylacrylamide) for drug delivery applications. [Internet] [Doctoral dissertation]. Georgia Tech; 2013. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/48947.
Council of Science Editors:
Chang K. Structural modification of poly(n-isopropylacrylamide) for drug delivery applications. [Doctoral Dissertation]. Georgia Tech; 2013. Available from: http://hdl.handle.net/1853/48947
22.
Mehrabadi, Marmar.
Effects of red blood cells and shear rate on thrombus growth.
Degree: PhD, Mechanical Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/53082
► Thrombosis formation upon rupture or erosion of an atherosclerotic plaque can lead to occlusion of arteries. An occlusive thrombus is the most common cause of…
(more)
▼ Thrombosis formation upon rupture or erosion of an atherosclerotic plaque can lead to occlusion of arteries. An occlusive thrombus is the most common cause of clinical events such as angina, myocardial infarction, ischemic attacks and strokes. Occlusive thrombi can cause ischemic cardiac arrest in less than an hour. Thrombosis formation requires rapid platelet accumulation rates exceeding thrombosis lysis and embolization rates. Hemodynamics greatly affects platelet accumulation rate through affecting platelet transport to the surface of a growing thrombus. The presence of red blood cells (RBCs) in blood increases platelet transport rate by several orders of magnitude compared to transport due to Brownian motion. Margination of platelets towards the vessel walls also results in higher platelet concentration at the RBC-depleted layer relative to the bulk. In this thesis, we studied the effects of hemodynamics on thrombus growth. We investigated the effects of important flow and particle properties on margination of particles in RBC suspensions by direct numerical simulation (DNS) of cellar blood flow. We derived a scaling law for margination length. Based on this scaling law, margination length increases cubically with channel height and is independent of shear rate. Using DNS, we verified the proposed scaling law for margination length in straight channels. We also showed that rigidity and size both lead to particle margination. We show that platelet margination can be explained by RBC-enhanced shear-induced diffusion of platelets in the RBC-filled region combined with platelet trapping in the RBC-free region. A simple continuum model is introduced based on the proposed mechanism. Using an experimental correlation for effective diffusivity in blood, the continuum model can recover experimental results from the literature over a wide range of tube diameters. We created an in vitro experimental model of thrombosis with and without RBCs. Surprisingly, we found that rapid thrombus growth does not require enhanced platelet transport in the presence of RBCs at high shear. Instead, our results suggest that thrombus growth rate at high shear is dependent on the availability of vWF-A1 domains as opposed to convective transport of platelets. Finally, we obtained empirical correlations for thrombus growth and lag time based on flow parameters by using an in vitro model of thrombosis. We developed a simple model for predicting thrombus formation using the obtained empirical correlations. We demonstrated the capability of the model in predicting thrombus formation over a wide range of experimental geometries. This model may be useful for designing blood-contacting devices to avoid unwanted thrombosis.
Advisors/Committee Members: Ku, David N. (advisor), Aidun, Cyrus K. (advisor), Ghiaasiaan, S. Mostafa (committee member), Tanaka, Kenichi (committee member), Champion, Julie A. (committee member).
Subjects/Keywords: Platelet transport; Margination; Thrombus growth; Blood flow; DNS; Red blood cells
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APA (6th Edition):
Mehrabadi, M. (2014). Effects of red blood cells and shear rate on thrombus growth. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/53082
Chicago Manual of Style (16th Edition):
Mehrabadi, Marmar. “Effects of red blood cells and shear rate on thrombus growth.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/53082.
MLA Handbook (7th Edition):
Mehrabadi, Marmar. “Effects of red blood cells and shear rate on thrombus growth.” 2014. Web. 03 Mar 2021.
Vancouver:
Mehrabadi M. Effects of red blood cells and shear rate on thrombus growth. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/53082.
Council of Science Editors:
Mehrabadi M. Effects of red blood cells and shear rate on thrombus growth. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/53082
23.
Park, Jonathan Taejoo.
Enzymatic reduction of nitro compounds to amines with nitroreductases.
Degree: PhD, Chemical and Biomolecular Engineering, 2014, Georgia Tech
URL: http://hdl.handle.net/1853/52267
► NRs are enzymes that catalyze the reduction of nitroaromatics to their corresponding nitroso, hydroxylamine, and, in limited cases, amine They have gathered interest in many…
(more)
▼ NRs are enzymes that catalyze the reduction of nitroaromatics to their corresponding nitroso, hydroxylamine, and, in limited cases, amine They have gathered interest in many scientific communities, and are currently actively researched bioremediation and prodrug activation. Here we attempt to utilize them for the purpose of synthesizing substituted aromatic amines that are found in a number of active pharmaceutical ingredients (APIs). As NRs described in the literature have varying product distribution ranges (from those that produce hydroxylamine to others that yield amine) several similar and different NRs were studied for their selectivity. Additionally, a quantitative structure-activity relationship (QSAR) was determined to characterize the substrate specificity of NRs. To employ the use of flavoenzymes in synthesis, multiple reaction- and protein-engineering approaches were devised. One scheme was to establish an enzymo-chemical synthesis where NRs were paired with reducing agents for a chemical reduction. Another method was to create a monomeric NR through directed evolution from ER scaffolds for future immobilization applications. Protein engineering techniques were also utilized on NADH oxidases which we characterized and developed for nicotinamide cofactor regeneration. As a whole, this dissertation expands our current understanding on NRs and demonstrates the possibility of using several flavoenzymes in the synthesis of organic molecules.
Advisors/Committee Members: Bommarius, Andreas S. (advisor), Gadda, Giovanni (committee member), Jones, Christopher W. (committee member), Champion, Julie A. (committee member), Spain, Jim C. (committee member).
Subjects/Keywords: Biocatalysis; Enzyme; Nitroreductase; Active pharmaceutical ingredient; Nitro; Reduction; Protein; Protein engineering
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APA (6th Edition):
Park, J. T. (2014). Enzymatic reduction of nitro compounds to amines with nitroreductases. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/52267
Chicago Manual of Style (16th Edition):
Park, Jonathan Taejoo. “Enzymatic reduction of nitro compounds to amines with nitroreductases.” 2014. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/52267.
MLA Handbook (7th Edition):
Park, Jonathan Taejoo. “Enzymatic reduction of nitro compounds to amines with nitroreductases.” 2014. Web. 03 Mar 2021.
Vancouver:
Park JT. Enzymatic reduction of nitro compounds to amines with nitroreductases. [Internet] [Doctoral dissertation]. Georgia Tech; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/52267.
Council of Science Editors:
Park JT. Enzymatic reduction of nitro compounds to amines with nitroreductases. [Doctoral Dissertation]. Georgia Tech; 2014. Available from: http://hdl.handle.net/1853/52267
24.
Sharma, Aditi.
Studies on amyloid aggregation and cross-species prion transmission.
Degree: PhD, Chemical and Biomolecular Engineering, 2018, Georgia Tech
URL: http://hdl.handle.net/1853/61123
► Ordered aggregation of proteins into amyloids (and their transmissible versions, prions) has been shown to result in several neurodegenerative diseases in humans and other mammals.…
(more)
▼ Ordered aggregation of proteins into amyloids (and their transmissible versions, prions) has been shown to result in several neurodegenerative diseases in humans and other mammals. While the effect of ions has been extensively studied in the context of measuring the stability of protein formulations and formation of disordered aggregates, there is limited information available on the effect of ions on the formation of ordered amyloid aggregates. In this thesis, we have investigated in detail the effect of presence of ionic co-solutes on the aggregation of amyloids.
Here, we have studied the efficiency of cross-transmission of the NM fragment of Sup35 prion protein, between three closely related species of the Saccharomyces sensu stricto group. Using anions of the Hofmeister series, we discerned the relative effects of protein sequence, seed conformation, and environment on the cross-species transmission of this protein. Further, through investigation of the aggregation of Amyloid beta-42 (Aβ42) and Sup35NM in the presence of anions we have uncovered interesting differences in their aggregation behavior suggesting key differences in the aggregation mechanism of these proteins. Lastly, we developed a computational model for amyloid aggregation kinetics and used it for global fitting of Sup35NM amyloid aggregation data. In all, this thesis expands the current knowledge of ion-specific effects on aggregation of amyloid proteins as well as of the mechanisms of amyloid aggregation.
Advisors/Committee Members: Bommarius, Andreas S. (advisor), Chernoff, Yury O. (committee member), Behrens, Sven H. (committee member), Champion, Julie A. (committee member), Finn, M. G. (committee member).
Subjects/Keywords: Protein aggregation; Amyloid; Prion; Hofmeister; Species barrier
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APA ·
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APA (6th Edition):
Sharma, A. (2018). Studies on amyloid aggregation and cross-species prion transmission. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/61123
Chicago Manual of Style (16th Edition):
Sharma, Aditi. “Studies on amyloid aggregation and cross-species prion transmission.” 2018. Doctoral Dissertation, Georgia Tech. Accessed March 03, 2021.
http://hdl.handle.net/1853/61123.
MLA Handbook (7th Edition):
Sharma, Aditi. “Studies on amyloid aggregation and cross-species prion transmission.” 2018. Web. 03 Mar 2021.
Vancouver:
Sharma A. Studies on amyloid aggregation and cross-species prion transmission. [Internet] [Doctoral dissertation]. Georgia Tech; 2018. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1853/61123.
Council of Science Editors:
Sharma A. Studies on amyloid aggregation and cross-species prion transmission. [Doctoral Dissertation]. Georgia Tech; 2018. Available from: http://hdl.handle.net/1853/61123
. 
Open Access Theses and Dissertations
