Retinal degeneration and chloride channels

视网膜变性和氯离子通道

• 批准号: 7462508
• 负责人: H. CRISS HARTZELL
• 金额: $ 38.69万
• 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/7462508
• 关键词: Address; Adolescent; Adult; Anions; Binding; Blindness; Cell membrane; Chloride Channels; Cultured Cells; Development; Disease; Disruption; Functional disorder; Genes; Homeostasis; Human; Inherited; Ion Channel; Ion Transport; Lesion; Light; Link; Liquid substance; Macular degeneration; Molecular Genetics; Mutation; Phosphorylation; Photoreceptors; Pigments; Proteins; Public Health; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinoids; Role; Structure of retinal pigment epithelium; Testing; Transgenic Mice; Uncertainty; Vitelliform macular dystrophy; insight; mutant; 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）：人类Bestrophin-1（HBEST1）的突变与最佳叶片状黄斑营养不良症（BVMD），成人发作的叶片叶片黄斑营养不良症（AVMD）和常染色体显着显性玻璃体固定菌属疾病（exectirs and Hearys and Hearys and nocation and eangy negtion and Hections and nocation and Hections negtions）未知。有强有力的证据表明HBEST1是一个阴离子（CL）通道。也有证据表明，HBEST1调节电压门控CA通道。该应用将检验以下假设：HBEST1是一种多功能蛋白，既是CL通道，可能具有质膜和细胞内功能，也是其他离子通道的调节剂，包括CA通道。假设Hbest1中的突变通过在视网膜色素上皮（RPE）水平上破坏视网膜的离子转运来产生视网膜疾病。我们建议，跨RPE的离子转运破坏会导致光感受器和RPE之间的空间中的流体含量异常和组成。这损害了RPE与感光体之间的相互作用，并有利于类维生素性衍生的色素的积累以及卵黄膜病变的发展。在此应用中，我们将使用分子，遗传学和电生理方法与用HBEST1和HBEST1突变体转染的培养细胞，转基因小鼠与中断或突变的HBEST1基因，以及新鲜蛋白溶性和培养的固定性接注的培养细胞的培养细胞一起研究HBEST1的功能和病理生理机制。这些研究不仅将提供有关叶片黄斑营养不良机制的重要见解，而且还将阐明离子在正常视网膜稳态上横跨视网膜色素上皮的作用。公共卫生相关性：这项研究涉及黄斑变性的机制，黄斑变性是失明的主要原因之一。具体而言，我们将研究称为BESTRophin的蛋白质功能障碍如何引起遗传性的少年发作形式的黄斑变性。我们预计这些研究将提供有关黄斑变性机制以及保持正常视网膜功能的机制的见解。