Most scientific understanding of epigenetic biology is in the field of development and cancer. In my early career period, I have been investigating various pathways of pro-inflammatory signaling in the retina and have recently discovered a powerful ability for biochemical modification of histones, a protein that complexes with DNA to form the nucleosome, to regulate the expression of specific inflammatory factors found in AMD. The striking changes in pro-inflammatory gene signatures that can be induced by inhibiting deacetylation of histones suggest that this pathway may be involved in the pathogenesis of AMD. Preliminary data demonstrated decreased expression of critical enzymes involved in these pathways in advanced dry AMD eyes and in experimental models of oxidative stress. Inhibition of histone deacetylation resulted in significant cytotoxic effects on the retinal pigment epithelium. In this project, I plan to rigorously dissect the role of histone deacetylase expression and function in the pathogenesis of dry AMD and RPE cell death using a novel mouse model and correlate in vitro studies. The proposed work will directly address a fundamental lack of knowledge on the role of histone deacetylases in the regulation of retinal inflammation and cell death making the work underway critically important in our search for effective targeted therapeutics for dry AMD.

Public Health Relevance

We are just beginning to gain scientific insight into the power of epigenetic modifications on genome-wide transcription. In this proposal, a highly significant role for histone deacetylase function in retinal pigment epithelial cell gene expression profiles and cell death in dry age-related macular degeneration will be studied. These data will provide important molecular insights to enhance our knowledge of the complex intersection of aging biology, epigenetics and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY028206-04
Application #
9904657
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2018-04-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
East Tennessee State University
Department
Type
DUNS #
051125037
City
Johnson City
State
TN
Country
United States
Zip Code
37614