Date of Award

8-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Integrated Program in Biomedical Sciences

Track

Neuroscience

Research Advisor

Monica M. Jablonski, Ph.D.

Committee

Edward Chaum, M.D., Ph.D. Dianna A. Johnson, Ph.D. Rajendra Raghow, Ph.D. Vanessa Morales-Tirado, Ph.D. Robert W. Williams, Ph.D.

Keywords

Flow cytometry, Glaucoma, Intraocular pressure, Retina, Retinal ganglion cells, Systems genetics

Abstract

Glaucoma refers to a group of conditions characterized by death of RGCs, increase in intraocular pressure is usually a precursor to glaucoma and irreversible optic neuropathy leads to visual impairment and blindness. Recent advances have seen a surge of new ideas and technologies to aid in the early detection, efficacious treatments and neuroprotection. Despite advances we face several challenges in understanding the pathophysiology of glaucoma. One of the many challenges scientists and ophthalmologists are facing is, to better understand IOP, its role in glaucomatous damage and design safer, more predictable IOP-lowering therapies. Another challenge is to find a practical method or develop tools to understand the molecular pathways to study RGC function and health to develop novel therapies for vision loss. This work leads to

three complementary insights on how to address these challenges. First, we used a novel systems genetics approach to identify and validate genetic modifiers of IOP using the enlarged BXD family of strains in combination with human GWAS glaucoma cohorts. This will pave the way for improved drug development tailored to individual genotypes for POAG. Second, we have combined systems genetics, bidirectional studies using multiple species, meta-analyses, immunohistochemistry, FACS sorting and gene knockdown studies to identify and validate the identity of a genetic modulator of Sncg, a gene that has been previously implicated in RGC death in glaucoma. Outcomes of the investigation may provide clues to understanding the molecular mechanisms that account for the degenerative changes in RGCs in glaucoma. Third, we optimized a feasible, reproducible, standardized flow cytometry-based protocol for the isolation and enrichment of homogeneous RGC. This will allow for future careful assessment of important cell specific pathways in RGC to provide mechanistic insights into the declining of visual acuity in aged populations and those suffering from retinal neurodegenerative diseases. Taken together these studies offer a concise outlook on use of integrated systems science, molecular and imaging technologies as a needs-led innovation in ophthalmology and visual health.

ORCID

http://orcid.org/0000-0003-1079-0950

DOI

10.21007/etd.cghs.2016.0410

Comments

One year embargo expires August 2017.

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