This proposal addresses the idea that activation of sirtuin-1 (Sirt1), a deacetylase that can regulate gene expression, will increase retinal ganglion cell (RGC) survival and visual system function in glaucoma. Activation of Sirt1 is essential to caloric restriction-induced reduction of age-related morbidity and increase of lifespan. This enzyme exerts its effects on metabolism, mitochondrial function, and other cell functions largely by deacetylation of histones and other proteins. Caloric restriction-induced protection against the normal age-related loss of retinal ganglion cells by Sirt1 activation suggests that the sirtuins are highly relevant to glaucoma. Growing evidence indicates that many, though not all, of the salutary benefits of caloric restriction can be induced by feeding with resveratrol, a sirtuin activator and natural compound, that is enriched in certain foods including red wine and peanuts. Our overall hypothesis is that increased Sirt1 activation will protect against glaucomatous damage in the retina, optic nerve, and brain of mouse models of glaucoma. Our general approach will be to investigate the effect of increasing Sirt1 activation by caloric restriction or by dietary resveratrol supplementation and to identify the role of Sirt1 by the use of transgenic mice lacking SIRT1 expression in their RGCs.
Specific Aims will be: 1) to determine whether Sirt1 activation will reduce RGC loss of Thy-1 gene expression and RGC death following optic nerve injury;2) to determine the biological basis of Sirt1-mediated RGC protection by evaluating retinal lipid peroxidation, mitochondrial integrity and function, and acetylation of proteins (including histones and transcription factors) critically involved in gene regulation;and 3) to determine whether Sirt1 activation preserves the structural integrity and function of the central visual system pathway.

Public Health Relevance

The present proposal evaluates the hypothesis that increased activation of sirtuin-1 protects against glaucomatous damage in the retina, optic nerve, and brain. The data generated will significantly enhance our basic understanding of sirtuin function in glaucoma, and assess whether targeting sirtuin-1 can lead to a novel glaucoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019692-02
Application #
8204632
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2011-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$639,587
Indirect Cost
$225,070
Name
University of California San Diego
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Weinreb, Robert N; Aung, Tin; Medeiros, Felipe A (2014) The pathophysiology and treatment of glaucoma: a review. JAMA 311:1901-11
Lindsey, James D; Duong-Polk, Karen X; Dai, Yi et al. (2013) Protection by an oral disubstituted hydroxylamine derivative against loss of retinal ganglion cell differentiation following optic nerve crush. PLoS One 8:e65966
Chindasub, Panida; Lindsey, James D; Duong-Polk, Karen et al. (2013) Inhibition of histone deacetylases 1 and 3 protects injured retinal ganglion cells. Invest Ophthalmol Vis Sci 54:96-102