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You searched for +publisher:"Georgia Tech" +contributor:("Yomi Oyelere"). Showing records 1 – 3 of 3 total matches.

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1. Guerrant, William. Targeted histone deacetylase inhibition.

Degree: PhD, Chemistry and Biochemistry, 2012, Georgia Tech

Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo. Advisors/Committee Members: Yomi Oyelere (Committee Chair), Donald Doyle (Committee Member), James Powers (Committee Member), Loren Williams (Committee Member), Yuhong Fan (Committee Member).

Subjects/Keywords: HDAC inhibitors; Drug design; Targeted drug delivery; HDAC; Histone deacetylase; Bifunctional inhibitors; Cancer therapy; Drug delivery systems; Cancer Treatment; Enzymes

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APA (6th Edition):

Guerrant, W. (2012). Targeted histone deacetylase inhibition. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/44907

Chicago Manual of Style (16th Edition):

Guerrant, William. “Targeted histone deacetylase inhibition.” 2012. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/44907.

MLA Handbook (7th Edition):

Guerrant, William. “Targeted histone deacetylase inhibition.” 2012. Web. 16 Jan 2021.

Vancouver:

Guerrant W. Targeted histone deacetylase inhibition. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/44907.

Council of Science Editors:

Guerrant W. Targeted histone deacetylase inhibition. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/44907


Georgia Tech

2. Orwig, Susan D. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.

Degree: PhD, Chemistry and Biochemistry, 2011, Georgia Tech

The inherited form of primary open angle glaucoma, a disorder characterized by increased intraocular pressure and retina degeneration, is linked to mutations in the olfactomedin (OLF) domain of the myocilin gene. Disease-causing myocilin variants accumulate within trabecular meshwork cells instead of being secreted to the trabecular extracellular matrix thought to regulate aqueous humor flow and control intraocular pressure. Like other diseases of protein misfolding, we hypothesize myocilin toxicity originates from defects in protein biophysical properties. In this thesis, the first preparative recombinant high-yield expression and purification system for the C-terminal OLF domain of myocilin (myoc-OLF) is described. To determine the relative stability of wild-type (WT) and mutant OLF domains, a fluorescence thermal stability assay was adapted to provide the first direct evidence that mutated OLF is folded but less thermally stable than WT. In addition, mutant myocilin can be stabilized by chemical chaperones. Together, this work provides the first quantitative demonstration of compromised stability among identified OLF variants and placing myocilin glaucoma in the context of other complex diseases of protein misfolding. Subsequent investigations into the biophysical properties of WT myoc-OLF provide insight into its structure and function. In particular, myoc-OLF is stable in the presence of glycosaminoglycans (GAGs), as well as over a wide pH range in buffers with functional groups reminiscent of such GAGs. Myoc-OLF contains significant â-sheet and â-turn secondary structure as revealed by circular dichroism analysis. At neutral pH, thermal melts indicate a highly cooperative transition with a melting temperature of ~55°C. A compact core structural domain of OLF was identified by limited proteolysis and consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. This construct also is capable of generating 3D crystals for structure determination. This data, presented in Chapter 3, inform new testable hypotheses for interactions with specific trabecular extracellular matrix components. To gain further insight into the biological function of myoc-OLF, a facile fluorescence chemical stability assay was designed to identify possible ligands and drug candidates. In the assay described in Chapter 4, the target protein is initially destabilized with a chemical denaturant and is tested for re-stabilization upon the addition of small molecules. The assay requires no prior knowledge of the structure and/or function of the target protein, and it is amendable to high-throughput screening. Application of the assay using a library of 1,280 compounds revealed 14 possible ligands and drug candidates for myoc-OLF that may also generate insights into myoc-OLF function. Due to the high â-sheet content of monomeric myoc-OLF and presence of an aggregated species upon myoc-OLF purification, the ability of myoc-OLF to form amyloid fibrils was suspected and… Advisors/Committee Members: Dr. Raquel Lieberman (Committee Chair), Dr. A. (Yomi) Oyelere (Committee Member), Dr. Al Merril (Committee Member), Dr. Loren Williams (Committee Member), Dr. Nicholas Hud (Committee Member), Dr. Roger Wartell (Committee Member).

Subjects/Keywords: Open-angle glaucoma; Pharmacological chaperones; High-throughput drug screen; Amyloid fibrils; Gaucher disease; Myocilin; Glaucoma; Eye Diseases; Eye Diseases Genetic aspects; Intraocular pressure; Body fluids Pressure; Eye

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APA (6th Edition):

Orwig, S. D. (2011). Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/45816

Chicago Manual of Style (16th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/45816.

MLA Handbook (7th Edition):

Orwig, Susan D. “Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease.” 2011. Web. 16 Jan 2021.

Vancouver:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Internet] [Doctoral dissertation]. Georgia Tech; 2011. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/45816.

Council of Science Editors:

Orwig SD. Biophysical and structural characterization of proteins implicated in glaucoma and Gaucher disease. [Doctoral Dissertation]. Georgia Tech; 2011. Available from: http://hdl.handle.net/1853/45816

3. Kasson, Tina Michelle Dreaden. High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair.

Degree: PhD, Chemistry and Biochemistry, 2012, Georgia Tech

Oxidative stress is a natural consequence of photosynthetic oxygen evolution and redox enzyme processes. Trp oxidation to N-formylkynurenine (NFK) is a specific, reactive oxygen species (ROS)-mediated reaction. This thesis work describes the identification and functional characterization of NFK in oxygen evolving Photosystem II (PSII). Although proteomics studies have confirmed NFK modifications in many types of proteins, limited knowledge on the biochemical significance exists. In vitro studies in thylakoids and PSII membranes were used to establish a correlation between oxidative stress, NFK formation, and photoinhibition. The in vivo effect of preventing Trp oxidation to NFK was assessed by site-directed mutation in the cyanobacteria Synechocystis sp. PCC 6803. This work provides insight into the role of NFK in photosynthetic oxygen evolution and photoinhibition. Based on the current knowledge of NFK, ROS, and repair, a new model is described. In this modified model for photoinhibition and repair, NFK plays a role in signaling for turnover of damaged proteins. NFK may play a similar role in replacement of damaged proteins in other systems. Advisors/Committee Members: Bridgette A. Barry (Committee Chair), David Collard (Committee Member), Ingeborg Schmidt-Krey (Committee Member), Wendy Kelly (Committee Member), Yomi Oyelere (Committee Member).

Subjects/Keywords: Tryptophan; Reactive oxygen species; Photosynthesis; Photosystem II; N-formylkynurenine; Synechocystis 6803; Amino acids; Plants Effect of light on

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

APA (6th Edition):

Kasson, T. M. D. (2012). High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair. (Doctoral Dissertation). Georgia Tech. Retrieved from http://hdl.handle.net/1853/45759

Chicago Manual of Style (16th Edition):

Kasson, Tina Michelle Dreaden. “High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair.” 2012. Doctoral Dissertation, Georgia Tech. Accessed January 16, 2021. http://hdl.handle.net/1853/45759.

MLA Handbook (7th Edition):

Kasson, Tina Michelle Dreaden. “High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair.” 2012. Web. 16 Jan 2021.

Vancouver:

Kasson TMD. High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair. [Internet] [Doctoral dissertation]. Georgia Tech; 2012. [cited 2021 Jan 16]. Available from: http://hdl.handle.net/1853/45759.

Council of Science Editors:

Kasson TMD. High light stress in photosynthesis: the role of oxidative post-translational modifications in signaling and repair. [Doctoral Dissertation]. Georgia Tech; 2012. Available from: http://hdl.handle.net/1853/45759

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