Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in developed countries and there are no treatments for the majority of patients. Early AMD is characterized by the formation of protein- and lipid-rich, sub-retinal pigmented epithelium (RPE) deposits. These deposits contain many constituents that are attributable to the activation of the complement cascade and immune cell activity. Indeed, genetic analyses demonstrate a strong link between AMD and complement components; in particular the soluble regulator, complement factor H (CFH), in which specific polymorphisms substantially increase the risk of AMD. To date efforts to understand how sub-RPE deposits, complement dysregulation and immune cell recruitment contribute to AMD have been limited by the lack of age-dependent models that faithfully recapitulate these pathogenic aspects of the disease.
The aim of the proposed studies is to leverage data recently derived using novel animal models of AMD that we have developed. These models invoke advanced age, complement dysregulation and lipid/cholesterol perturbation, all known contributors to human AMD risk. We have identified the association of CFH levels in the vasculature, and in the RPE/Bruch's membrane/choroid complex, with the size and frequency of sub-RPE deposit formation and with local monocyte recruitment. Additionally, data derived from these models points to a novel role for CFH in AMD pathogenesis that is mediated through competitive interactions with proteoglycans and lipoproteins in Bruch's membrane. Based on these observations, we hypothesize that CFH dysfunction contributes to AMD pathogenesis by 2 mechanisms: (1) Decreased local concentrations of CFH lead to elevated levels of complement activation in the RPE/Bruch's membrane/choroid complex which induce pathological recruitment of monocytes. These result in compromised RPE and choriocapillaris (CC) function and concomitant vision loss; and (2) Changes in proteoglycans with age results in reduced competition by CFH for lipoprotein binding sites on heparan sulfate associated with Bruch's membrane and contributes to lipid accumulation in sub-RPE deposits and Bruch's membrane. The studies proposed in Aim 1 will test if blocking infiltrating monocyte recruitment protects against development of AMD-like pathology in the RPE/Bruch's membrane/choroid complex and consequent vision loss.
Aim 2 will assess the nature of competitive binding between CFH and lipoproteins for sites in Bruch's membrane. Studies proposed in Aim 3 will directly interrogate the contribution of the human AMD-risk associated CFH variant to the development of an AMD phenotype in humanized CFH mice. These studies will provide insights into the influence of CFH on sub-RPE deposit formation, the role of CFH in the recruitment of immune cells and their potential contribution to AMD pathogenesis, as well as the relationship of interactions between CFH and lipoproteins at the level of Bruch's membrane with the development of dry AMD.

Public Health Relevance

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among elderly Americans, which has a devastating socioeconomic burden. Notwithstanding diminishing quality of life, the 2014 economic burden of vision loss in the U.S. is $145 billion, of which AMD is a major proportion. In AMD, there is a strong genetic influence of components of the complement system that regulate innate immunity. Our proposed studies are designed to provide a biochemical explanation for the genetic basis of complement dysregulation in AMD. The proposed research is relevant to the National Eye Institute high priority research area, Intersection of Aging & Biological Mechanisms of Eye Disease, as well as to the National Institute on Aging research goal to Improve Understanding of Healthy Aging and Disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026161-03
Application #
9402623
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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