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: 8340877
• 负责人: Seongjin Seo
• 金额: $ 44.5万
• 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/8340877
• 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. PUBLIC HEALTH RELEVANCE: Inherited retinal degenerations are one of the major causes of early onset blindness. These disorders are often caused by a loss of proteins that are involved in protein transport to primary cilia. The proposed research will provide insight into the molecula mechanisms of retinal degeneration caused by mutations in ciliary trafficking genes, so that therapies can be developed to prevent vision losses due to these diseases.

描述（由申请人提供）：光感受器变性是早期发作失明的主要原因。积累的证据表明，睫状运输基因的突变是遗传感光者变性的最常见原因之一。然而，由于缺陷型睫毛贩运而导致的光感受器变性的基本机制知之甚少。拟议的研究的长期目标是通过了解与缺陷型睫毛交通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）是一种与纤毛运输缺陷相关的人类遗传疾病，导致感光受体变性。最近，我们和其他人表明，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部和外部段之间运输特定的货物蛋白，并且这些cargos的运输缺陷是视网膜变性的病理生理学的基础。在该项目中，我们将通过追求以下特定目的来鉴定光感受器细胞中的BBS蛋白陈述，并提高我们对BBS中光感受器退化的潜在分子机制的理解：1）使用Tandem MICES和TANDEM亲和力纯化，使用定量的蛋白质分析，2）识别BBSOME cargos和调节剂，并确定bsbsome cargos and congulators，2） 3）阐明了BBSOME CARGOS和调节剂在疾病机制方面的生物学意义。在初步研究中，我们从与BBS相关的几个组织中分离并鉴定出BBSOME相互作用的蛋白质。我们还发现，BBS外部细分市场中有几种与色素性视网膜炎或Leber先天性症的蛋白质降低。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。这项研究最终将提供有价值的洞察力，了解BBS蛋白保持正常感光细胞功能的基本生物学机制，并作为开发基于机制的纤毛病变相关视网膜变性的知识库。 公共卫生相关性：继承的视网膜变性是早期发作失明的主要原因之一。这些疾病通常是由于蛋白质转运到原发性纤毛的蛋白质的损失而引起的。拟议的研究将洞悉由纤毛运输基因突变引起的视网膜变性的分子机制，以便可以开发出疗法以防止由于这些疾病而导致视力丧失。