Diabetic retinopathy remains the leading cause of blindness in working age adults. Currently, there are no approved and demonstrated treatments for diabetic retinopathy aside from insulin replacement therapy and blood pressure control. Recent longitudinal study reports have demonstrated that despite achieving stable blood glucose levels and HbA1c control, patients formerly under non-intensive insulin therapy continue to have a higher rate of developing diabetic retinopathy, and other complications. This provides the first large-scale clinical evidence for the hypothesis of metabolic memory, in which a period of poor diabetes management continues to impact development of retinopathy and other complications for years after good control has been achieved. Understanding the role of metabolic memory in complication development is vitally needed as the memory phenomenon is obviously not overcome by current treatment regimens. This clinical phenomenon also leads to the questions of what molecular events occur during poor control and how do these events persist for years after good glycemic control is established. This proposal seeks to address this issue through an investigation of the hypothesis that poor control causes epigenomic changes that are not fully reversed with improved diabetes management. In the proposed studies we will define retinal gene promoter DNA methylation and associated chromatin modifications in the context of diabetes with variable glycemic control. We will then use bioinformatic tools to compare the epigenetic state to retinal gene/protein expression. Epigenetic changes will be confirmed by orthogonal methods and the resulting transcript and protein expression changes will be localized to specific retinal layers and cell types. Lastly the processes that regulate DNA methylation and histone modification will be examined. These studies will serve as the basis for future interventional studies which seek to maintain or return the normal retina epigenetic state as well as mechanistic studies investigating how specific genes are targeted for epigenetic modifications during hyperglycemia.

Public Health Relevance

Diabetic retinopathy remains the leading cause of blindness in working age adults and recent clinical studies have demonstrated that despite achieving good diabetes control, patients with previously poor diabetes control continue to have a higher rate of developing diabetic retinopathy and other complications. This study will investigate the potential epigenetic basis of this metabolic memory phenomenon. Understanding the role of epigenetic changes in diabetic retinopathy will open new avenues for development of therapies which seek to maintain or restore the pre-diabetic state.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021716-02
Application #
8304190
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$344,250
Indirect Cost
$119,250
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Masser, Dustin R; Berg, Arthur S; Freeman, Willard M (2013) Focused, high accuracy 5-methylcytosine quantitation with base resolution by benchtop next-generation sequencing. Epigenetics Chromatin 6:33
Kaiser, James M; Imai, Hisanori; Haakenson, Jeremy K et al. (2013) Nanoliposomal minocycline for ocular drug delivery. Nanomedicine 9:130-40