The overall goal of this research is to better understand the role of ocular lipofuscin in macular degeneration. In doing so we develop clinically relevant ways to inhibit lipofuscin formation (as possible interventions for macular degeneration) and develop animal models of lipofuscin-induced macular degeneration.
The specific aims of this application are:
AIM 1) elucidate the relationship between lipofuscin and retinal health and the mechanism of lipofuscin formation: a) determine whether slowing lipofuscin biosynthesis can prevent ocular aging and vision loss in rodent models of macular degeneration;b) determine whether increasing the concentration of vitamin A dimers in the RPE leads to the formation of lipofuscin granules and drusen;and c) determine whether animals models of macular degeneration can be generated by rapidly increasing lipofuscin pigments;
and AIM 2) elucidate pharmacokinetics vitamin A and vitamin A dimers in the eye: a) determine the time it takes to swap vitamin A for D3-vitamin A in the outer segments;b) establish the RPE half life of vitamin A dimers;c) determine whether the rate of lipofuscin pigment biosynthesis increases with age or whether lipofuscin pigments themselves "accumulate" with age, and;d) compare visual cycle kinetics of vitamin A vs. D3-vitamin A. We will achieve these specific aims by slowing down or speeding up lipofuscin formation in animals, using novel methods developed in our lab, and correlating eye health to lipofuscin concentration. In evaluating eye health in response to changes in lipofuscin we employ standard methods such as, tissue histology, fundus autofluorescence, electroretinogram measurements, inflammatory status and quantification of vitamin A dimers. For the elucidation of the ocular pharmacokinetics of vitamin A and its dimers we track their fate and/or biosynthesis using deuterium or tritium labeled species. We intend to show that the biosynthesis of vitamin A dimers (also called or lipofuscin pigments or A2E and ATR-dimer) is an early and critical step in the formation of lipofuscin granules (or deposits) in the RPE cell layer of the eye;that lipofuscin granules lead to the formation of drusen (or drusen like material) and ultimately cell death and vision impairment. We intend to show that stopping the biosynthesis of vitamin A dimers is an effective clinical strategy to stopping the formation of lipofuscin and drusen, as a method to stop the progression of the most prevalent forms of macular degeneration. We intend to gather evidence to show that the administration of D3-vitamin A is a safe, practical, method to prevent the progression of several forms of macular degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021207-04
Application #
8607956
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$362,250
Indirect Cost
$137,250
Name
Columbia University (N.Y.)
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Mihai, D M; Washington, I (2014) Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells. Cell Death Dis 5:e1348
Mihai, Doina M; Jiang, Hongfeng; Blaner, William S et al. (2013) The retina rapidly incorporates ingested C20-Dýýý-vitamin A in a swine model. Mol Vis 19:1677-83