Age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) cells leading to their progressive dysfunction and eventually atrophy in AMD are not known. Multiple epidemiological, biochemical, and histological studies highlight the role of altered cholesterol metabolism in the pathogenesis of AMD. The liver x receptor is an important regulator of reverse cholesterol transport. Beyond this established function it has also been shown to regulate inflammation, cell metabolism and apoptosis. We have recently found that aged LXR knockout mice develop cardinal features of dry AMD including accumulation of cholesterol and neutral lipids within Bruch's membrane and development of significant sub-RPE deposits. Herein we propose to investigate the role of two modulators of LXR in RPE biology and pathogenesis of AMD.
Age-related macular degeneration (AMD) affects 30% of individuals over the age of 65 years and is the leading cause of vision loss in the Western World. It is a multi-factorial disease with a complex etiology. Given, currently there are no therapeutic options available for the `dry' forms of the disease, understanding the mechanisms underlying cell injury, deposit formation, and identifying the signaling pathways that are key to disease initiation and progression will open up new avenues for therapeutic strategies. The objective of this grant is to study the liver x receptor beyond its classical role in regulation cholesterol metabolism, in the development of AMD. The proposed studies are relevant to the NEI high priority research area, ?Intersection of Aging and Biological Mechanisms of Eye Disease?, as well as to the NIA research goal to ?Improve Understanding of Healthy Aging and Disease?.
|Ban, Norimitsu; Lee, Tae Jun; Sene, Abdoulaye et al. (2018) Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss. JCI Insight 3: