Molecular Mechanisms Underlying Macular Degenerations

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DESCRIPTION (provided by applicant): The goal of this proposal is to understand molecular mechanisms underlying macular degeneration (MD). Macular degenerations are a phenotypically and genotypically heterogenous group of blinding disorders characterized by central vision loss associated with atrophy of retinal pigment epithelium with or without choroidal neovascularization. Understanding the mechanisms underlying these debilitating diseases will help design therapeutic strategies to delay the onset, slow the progression, prevent or treat the condition. We have identified mutations in two novel genes: (1) Elongation very long-chain fatty acid - 4 (ELOVL4) and (2) C1q and tumor necrosis factor related protein 5 (C1QTN5/CTRP5). These mutations occur in families with early-onset atrophic macular degeneration or Stargardt-like dominant macular degeneration (STGD3) and late-onset autosomal dominant hemorrhagic macular degeneration respectively. We propose to study the mechanisms underlying normal photoreceptor maintenance and how disruptions of these mechanisms result in macular degenerations by focusing on the ELOVL4 and CTRP5 genes and their mutations. For each disease our hypothesis is: (a) the wild type protein is critical for the normal function, and (b) abnormal protein production disrupts the retina. We will also test the hypothesis that nutritional intervention delays or slows the progression of STGD3. We will test these hypotheses using cell culture system and animal models. We chose these two distinct forms of macular degenerations because we believe that they offer a unique opportunity to understand functional roles of the genes involved and, thus, to understand other forms of MD.