Retinal degeneration and chloride channels

视网膜变性和氯离子通道

• 批准号: 7585216
• 负责人: H. CRISS HARTZELL
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585216
• 关键词: Address; Adolescent; Adult; Anions; Binding; Blindness; Cell membrane; Chloride Channels; Cultured Cells; Development; Disease; Functional disorder; Genes; Homeostasis; Human; Inherited; Ion Channel; Ion Transport; Lesion; Light; Link; Liquid substance; Macular degeneration; Molecular Genetics; Mutation; Phosphorylation; Photoreceptors; Pigments; Proteins; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinoids; Role; Structure of retinal pigment epithelium; Testing; Transgenic Mice; Uncertainty; Vitelliform macular dystrophy; insight; mutant; public health relevance; voltage

DESCRIPTION (provided by applicant): Mutations in human bestrophin-1 (hBest1) are associated with Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC), but the precise function of hBest1 remains in doubt and the mechanisms linking hBest1 dysfunction with disease are unknown. There is strong evidence that hBest1 is an anion (Cl) channel. There is also evidence that hBest1 regulates voltage-gated Ca channels. This application will test the hypothesis that hBest1 is a multifunctional protein that is both a Cl channel, possibly with both plasma membrane and intracellular functions, and a regulator of other ion channels, including Ca channels. Mutations in hBest1 are hypothesized to produce retinal disease by disrupting ion transport in the retina at the level of the retinal pigment epithelium (RPE). We suggest that disruption of ion transport across the RPE results in abnormal fluid content and composition in the space between photoreceptors and RPE. This compromises the interaction between RPE and photoreceptors and favors accumulation of retinoid-derived pigments and development of vitelliform lesions. In this application, we will investigate the functions and pathophysiological mechanisms of hBest1 using a combination of molecular, genetic, and electrophysiological approaches with cultured cells transfected with hBest1 and hBest1 mutants, transgenic mice with disrupted or mutant hBest1 genes, and freshly-isolated and cultured retinal pigment epithelial cells. These studies will not only provide important insights into the mechanisms of vitelliform macular dystrophies, but will also shed light on the role of ion transport across the retinal pigment epithelium on normal retinal homeostasis. PUBLIC HEALTH RELEVANCE: This research addresses the mechanisms of macular degeneration, one of the major causes of blindness. Specifically, we will investigate how dysfunction of a protein called bestrophin causes an inherited juvenile-onset form of macular degeneration. We expect that these studies will provide insights into the mechanisms of macular degeneration and the mechanisms that maintain normal retinal function.

描述（由申请人提供）：人 bestropin-1 (hBest1) 突变与最佳卵黄状黄斑营养不良 (BVMD)、成人发病的卵黄状黄斑营养不良 (AVMD) 和常染色体显性玻璃体视网膜脉络膜病变 (ADVIRC) 相关，但其确切功能hBest1 仍然存在疑问，并且 hBest1 功能障碍与疾病之间的联系机制尚不清楚。有强有力的证据表明 hBest1 是阴离子 (Cl) 通道。还有证据表明 hBest1 调节电压门控 Ca 通道。该应用将测试以下假设：hBest1 是一种多功能蛋白，它既是 Cl 通道（可能具有质膜和细胞内功能），又是其他离子通道（包括 Ca 通道）的调节器。据推测，hBest1 突变会破坏视网膜色素上皮 (RPE) 水平的离子传输，从而产生视网膜疾病。我们认为，穿过 RPE 的离子传输中断会导致光感受器和 RPE 之间的空间中液体含量和成分异常。这损害了 RPE 和光感受器之间的相互作用，并有利于类维生素A衍生色素的积累和卵黄样病变的发展。在此应用中，我们将结合分子、遗传和电生理学方法，研究 hBest1 的功能和病理生理学机制，包括转染 hBest1 和 hBest1 突变体的培养细胞、hBest1 基因破坏或突变的转基因小鼠以及新鲜分离和培养的细胞。视网膜色素上皮细胞。这些研究不仅将为卵黄样黄斑营养不良的机制提供重要的见解，还将阐明跨视网膜色素上皮的离子运输对正常视网膜稳态的作用。公众健康相关性：这项研究探讨了黄斑变性的机制，黄斑变性是失明的主要原因之一。具体来说，我们将研究一种称为斑黄蛋白的蛋白质功能障碍如何导致遗传性青少年发病形式的黄斑变性。我们期望这些研究将为黄斑变性的机制和维持正常视网膜功能的机制提供见解。