Project title: Neuroprotective Role of Sirt6 in Glaucoma SUMMARY Glaucoma is the second leading cause of irreversible blindness worldwide. It is characterized as progressive retinal ganglion cell (RGC) death and optic nerve degeneration. Strong risk factors for glaucoma include elevated intraocular pressure (IOP), age and genetic background. Among them, only IOP is well-studied and serves as the only treatable target for glaucoma. However, lowering IOP does not always stop the progression of glaucoma. It is urgent to identify other mechanisms of neuropathy in glaucoma for therapeutic intervention. Sirtuin (Sirt) 6 is a member of the Sirts that are evolutionarily conserved nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases and share homolog with yeast Sir2 protein that critically regulates lifespan of yeast. It is a histone H3 lysine 9 (H3K9) and H3K56 deacetylase which represses the transcription activities of several transcription factors involved in aging and inflammation, promotes DNA repair, prevents genomic instability and maintains glucose homeostasis. These multiple functions of Sirt6 position it as a key anti-aging molecule. Sirt6 is expressed in the retina but its role in glaucoma is unknown. This application will integrate a series of novel approaches including our newly developed Sirt6 global and conditional knockout /overexpression mice, AAV2-mediated gene knockdown, clinic-relevant non-invasive imaging and functional tests, state-of-the-art imaging to test the hypothesis that Sirt6 plays a key role in the prevention of dysfunction/degeneration of retinal ganglion cells and their axons in glaucoma. We will: 1) test the hypothesis that loss of Sirt6 causes pathological changes in the retina and optic nerve resembling glaucoma; 2) test the hypothesis that boosting Sirt6 expression prevents pathological changes in the retina and optic nerve in IOP elevation-induced glaucoma. Completion of the proposed studies will provide important new knowledge that may guide the development of novel therapies for glaucoma. This proposal is in line with vision research priorities identified in the NEI Publication, ?Vision Research: Needs, Gaps, & Opportunities?: 1) Determine the mechanisms by which risk factors, such as age and prior glaucomatous injury, influence susceptibility of remaining RGC axons to elevated IOP; 2) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology; 3) Explore neuroprotection as an approach for prolonging RGC function and survival.

Public Health Relevance

Sirt6 is a NAD-dependent histone H3 lysine 9 (H3K9) and H3K56 deacetylase which represses many aging processes. We propose studies to understand the role of Sirt6 in retinal ganglion cell injury and optic nerve degeneration in glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY031054-01
Application #
9867317
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2020-06-01
Project End
2025-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Med Br Galveston
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555