Molecular Mechanisms Underlying Macular Degenerations

描述(由申请人提供)：本提案的目标是了解黄斑变性(MD)的分子机制。黄斑变性是一组表型和遗传异质性的致盲性疾病，其特征是中心视力丧失，伴有或不伴有脉络膜新生血管的视网膜色素上皮萎缩。了解这些衰弱疾病的潜在机制将有助于设计治疗策略，以延迟发病，减缓进展，预防或治疗这种疾病。 我们已经发现了两个新基因的突变：(1)超长链脂肪酸-4(ELOVL4)和(2)C1q和肿瘤坏死因子相关蛋白5(C1QTN5/CTRP5)。这些突变分别发生在早发性萎缩性黄斑变性或Stargardt样显性黄斑变性(STGD3)和晚发性常染色体显性出血性黄斑变性家系中。 我们建议通过研究ELOVL4和CTRP5基因及其突变来研究正常光感受器维持的机制以及这些机制的破坏如何导致黄斑变性。对于每种疾病，我们的假设是：(A)野生型蛋白质对正常功能至关重要，(B)异常蛋白质产生扰乱视网膜。我们还将测试营养干预延迟或减缓STGD3进展的假设。我们将使用细胞培养系统和动物模型来验证这些假设。 我们选择了这两种不同的黄斑变性形式，因为我们相信它们提供了一个独特的机会来了解相关基因的功能作用，从而了解其他形式的MD。

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.