Angiogenesis, the formation of new blood vessels, is a regulated process determined by the local balance of endogenous stimulators versus inhibitors. Angiogenesis-dependent diseases are the major cause of blindness in the developed world. Epidemiological studies have shown that the incidence of exudative age-related macular degeneration (ARMD) is race dependent and highly correlated to pigmentation levels. Compared to white people, lowly-pigmented individuals, the prevalence of choroidal neovascularization is 55% lower in black people, highly-pigmented individuals and 46% lower in Asian Americans. The studies outlined in our proposal are aimed at understanding the role of melanocytes in ARMD. We have previously shown that melanocytes with low pigmentation have high expression levels of a novel angiogenic factor known as Fibromodulin (FMOD). We have confirmed FMOD's angiogenic activity in several in vivo angiogenesis models. The goal of this project is to elucidate the cellular mechanisms by which melanocytes induce pathological angiogenesis via FMOD. We now propose to: (1) Investigate the physiological conditions and molecular stimulators that increase FMOD expression by melanocytes, including identification of transcription factors that activate FMOD expression; (2) Investigate FMOD receptor-mediated signal transduction in angiogenesis by characterizing the FMOD - ROR2 interaction in endothelial cells; and (3) Establish how melanocytes promote angiogenesis via FMOD in various ocular animal models and human donor eyes. Understanding the role of melanocytes and melanocyte-secreted FMOD in vascular diseases would advance our understanding of the melanocytic microenvironment and offer novel targets for personalized treatment of angiogenesis-dependent diseases.

Public Health Relevance

Inappropriate blood vessel growth (pathological angiogenesis) in ocular disease is the main cause of blindness in the western world. We have discovered the mechanism by which the incidence of onset and severity of age-related macular degeneration (ARMD) are highly correlated with pigmentation disparities seen between races. Our studies are aimed at understanding the role of melanocytes in ARMD and they have the potential to improve both prognostic and therapeutic approaches to blinding angiogenic ocular diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024046-02
Application #
9480850
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code