Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age in the industrialized world. Vision loss in advanced AMD is either due to pathologic angiogenesis called choroidal neovascularization (CNV) or from loss of the retinal pigmented epithelium and overlying photoreceptor neurons in geographic atrophy. CNV tends to be catastrophic and accounts for about 80-90% of severe vision loss in AMD. Macrophage-mediated inflammation plays a critical role in the pathogenesis of CNV in AMD. The aging macrophage manifests its dysfunction in AMD by altered activation and polarization. The regulatory mechanisms that govern gene expression changes within macrophages are poorly characterized. MicroRNAs regulate gene expression at a global level but with cellular specificity and do so by mRNA degradation and translational repression. We propose to examine which miRNAs are altered in the aging macrophage, identify the specific gene targets that they regulate and assess the effects of modifying both the miRNA and genes in macrophages on their fate, function and ability to regulate CNV. This could be especially insightful as it might confirm age as a continuous variable that can be quantitatively regulated at an intrinsic level. We hope to identify novel miRNA, genes and molecular pathways that could be therapeutically targeted in AMD to prevent vision loss in this devastating disease.

Public Health Relevance

Altered macrophage polarization is a pathogenic event in the aging of the immune system. It is also critical to the pathobiology of diverse diseases of aging including age-related macular degeneration (AMD). Although abnormalities in macrophage function in AMD have been phenotypically characterized, the molecular pathways that regulate this phenotype are unclear. The current proposal will focus on understanding how small non-coding microRNAs regulate aging macrophage gene expression. Understanding the regulation of genes involved in AMD pathogenesis will open up novel avenues for targeted therapy for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY019287-06A1
Application #
9594879
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2010-09-30
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Park, Changwon; Lee, Tae-Jin; Bhang, Suk Ho et al. (2016) Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86-96

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