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（由申请人提供）：光感受器变性是早发性失明的主要原因。越来越多的证据表明，纤毛运输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，由于纤毛运输缺陷导致光感受器退化的潜在机制尚不清楚。拟议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。巴代-比德尔综合症 (BBS) 是一种与纤毛运输缺陷相关的人类遗传性疾病，可导致光感受器变性。最近，我们和其他人已经证明，BBS 蛋白参与纤毛和质膜之间特定货物蛋白的运输，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 蛋白在感光细胞的内节和外节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学的基础。在这个项目中，我们将通过追求以下具体目标来鉴定感光细胞中的 BBS 蛋白货物，并加深我们对 BBS 中感光细胞变性的潜在分子机制的理解：1）使用转基因小鼠和串联亲和纯化来鉴定 BBSome 货物和调节剂， 2) 使用 iTRAQ 对 BBS 视网膜的光感受器外节进行定量蛋白质组学分析，以及 3) 阐明 BBSome 货物和调节剂的生物学意义疾病机制。在初步研究中，我们从与 BBS 相关的几个组织中分离并鉴定了 BBSome 相互作用蛋白。我们还发现，BBS 外节中与色素性视网膜炎或莱伯先天性黑蒙相关的几种蛋白质减少。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。这项研究最终将为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，并作为开发基于机制的纤毛病相关视网膜变性疗法的知识库。