Molecular Pathophysiology of Retinal Degeneration in Bardet-Biedl Syndrome

Bardet-Biedl 综合征视网膜变性的分子病理生理学

• 批准号: 8534137
• 负责人: Seongjin Seo
• 金额: $ 39.68万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534137
• 关键词: Accounting; Affinity; Affinity Chromatography; Animals; Bardet-Biedl Syndrome; Biochemical; Biological; Blindness; Cell membrane; Cell physiology; Cells; Cilia; Clinical Management; Data; Defect; Development; Disease; Etiology; Functional disorder; Genes; Genetic; Goals; Hereditary Disease; Human Genetics; Inherited; Knock-in Mouse; Knowledge; Leber' s amaurosis; Methods; Modification; Molecular; Mutation; Patients; Photoreceptors; Proteins; Proteome; Proteomics; Recombinants; Research; Retina; Retinal Degeneration; Retinitis Pigmentosa; Role; Testing; Therapeutic; Tissues; Transgenic Animals; Transgenic Mice; Work; base; ciliopathy; early onset; inherited retinal degeneration; insight; knowledge base; novel; photoreceptor cell outer segment; photoreceptor degeneration; prevent; protein transport; trafficking

DESCRIPTION (provided by applicant): Photoreceptor degeneration is a major cause of early onset blindness. Accumulating evidence indicates that mutations in ciliary trafficking genes are one of the most common causes of inherited photoreceptor degeneration. Yet, the underlying mechanisms of photoreceptor degeneration due to defective ciliary trafficking are poorly understood. The long-term objective of the proposed research is to advance therapeutic potential by understanding the molecular mechanisms of photoreceptor degeneration associated with defective ciliary trafficking. Bardet-Biedl Syndrome (BBS) is a human genetic disorder associated with ciliary trafficking defects that leads to photoreceptor degeneration. Recently, we and others have shown that BBS proteins are involved in the transport of specific cargo proteins between the ciliary and plasma membranes and that identification of BBS protein cargos has significant implications for the etiology of BBS. Here, we hypothesize that BBS proteins transport specific cargo proteins between the inner and outer segments of the photoreceptor cells and that the trafficking defects of these cargos underlie the pathophysiology of retinal degeneration. In this project, we will identify BBS protein cargos in the photoreceptor cells and advance our understanding of the underlying molecular mechanisms of photoreceptor degeneration in BBS by pursuing the following specific aims: 1) Identify BBSome cargos and regulators using transgenic mice and tandem affinity purification, 2) Perform quantitative proteomic analysis of photoreceptor outer segments from BBS retina using iTRAQ, and 3) Elucidate the biological significance of BBSome cargos and regulators with respect to disease mechanisms. In preliminary studies, we isolated and identified BBSome interacting proteins from several tissues relevant to BBS. We also found that several proteins that are associated with retinitis pigmentosa or Leber congenital amaurosis are decreased in the BBS outer segment. We will further extend these findings and elucidate the molecular basis of photoreceptor degeneration in BBS. This research will ultimately provide valuable insight into the basic biological mechanisms by which BBS proteins maintain normal photoreceptor cell function and also serve as a knowledge base for the development of mechanism-based therapies for ciliopathy-related retinal degenerations.

描述（申请人提供）：光感受器变性是早期失明的主要原因。越来越多的证据表明，纤毛转运基因的突变是遗传性光感受器变性的最常见原因之一。然而，由于纤毛运输缺陷引起的光感受器变性的潜在机制尚不清楚。该研究的长期目标是通过了解与纤毛运输缺陷相关的光感受器变性的分子机制来提高治疗潜力。Bardet-Biedl综合征（BBS）是一种人类遗传性疾病，与睫状体运输缺陷相关，导致光感受器变性。最近，我们和其他人已经证明BBS蛋白参与了特定货物蛋白在纤毛膜和质膜之间的运输，并且BBS蛋白货物的鉴定对BBS的病因学具有重要意义。在这里，我们假设BBS蛋白在光感受器细胞的内外段之间运输特定的货物蛋白，并且这些货物的运输缺陷是视网膜变性的病理生理基础。在本项目中，我们将在感光细胞中识别BBS蛋白货物，并通过追求以下具体目标来推进我们对BBS光感受器退化的潜在分子机制的理解：1)利用转基因小鼠和串联亲和纯化技术鉴定BBSome cargo和regulatory， 2)利用iTRAQ技术对BBS视网膜光感受器外段进行定量蛋白质组学分析，3)阐明BBSome cargo和regulatory在疾病机制中的生物学意义。在初步研究中，我们从几种与BBS相关的组织中分离并鉴定了一些相互作用的蛋白。我们还发现，与视网膜色素变性或Leber先天性黑朦相关的几种蛋白质在BBS外节段减少。我们将进一步扩展这些发现并阐明BBS中光感受器变性的分子基础。这项研究将最终为BBS蛋白维持正常感光细胞功能的基本生物学机制提供有价值的见解，并为开发基于机制的治疗纤毛病相关视网膜变性的方法提供知识基础。