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

基本信息

批准号：
9235611
负责人：
Seongjin Seo
金额：
$ 38.13万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9235611
关键词：
Affect Bardet-Biedl Syndrome Blindness Cell Death Cell physiology Cells Child Cilia Data Development Disease Event Failure Follow-Up Studies Foundations Functional disorder Funding Genes Goals Grant Hereditary Disease Human Genetics Knockout Mice Mediating Membrane Fusion Molecular Mus Mutant Strains Mice Mutation Outcome Study Pathogenesis Pathogenicity Patients Photoreceptors Play Proteins Rana Reporter Research Retina Retinal Degeneration Retinal Diseases Rhodopsin Role SNAP receptor Severities Stress Structure Testing Therapeutic Intervention Transgenic Mice Transgenic Organisms Variant Vision base differential expression early onset effective therapy inherited retinal degeneration insight mouse model multicatalytic endopeptidase complex mutant novel photoreceptor degeneration programs protein transport trafficking treatment strategy young adult

项目摘要

Abstract Mutations disrupting ciliary assembly and trafficking are a common cause of inherited retinal degenerations, causing early-onset severe blindness. Bardet-Biedl syndrome (BBS) is one of the human genetic diseases associated with defective ciliary trafficking and photoreceptor degeneration. However, details of the patho-mechanisms underlying photoreceptor degeneration in BBS are largely unknown and no effective treatment options have been developed. The long-term goal of this research program is to elucidate the molecular and cellular mechanisms of photoreceptor degeneration in BBS and develop therapeutic interventions to preserve vision in BBS patients. Our prior study determined that accumulation of proteins in the outer segment (OS) is likely the primary cause of photoreceptor degeneration in BBS, representing a novel mechanism of photoreceptor degeneration. During the next grant cycle, we will explore how protein accumulation in the OS induces photoreceptor degeneration. Our preliminary data suggest that OS accumulation/sequestration of Stx3 (a SNARE protein facilitating membrane fusion events) and proteasomal overload stress are involved. The proposed study will determine how these factors contribute to photoreceptor degeneration in BBS. The outcome of this study will greatly advance our understanding of the cilia-related retinopathies and provide an important foundation for the development of mechanism-based therapies.

抽象的破坏睫状体组装和运输的突变是遗传性视网膜的常见原因变性，导致早发性严重失明。 Bardet-Biedl 综合征 (BBS) 是人类的一种与睫状体运输缺陷和光感受器变性相关的遗传病。然而， BBS 中光感受器变性的病理机制细节在很大程度上尚不清楚，并且尚未开发出有效的治疗方案。该研究计划的长期目标是阐明 BBS 中光感受器变性的分子和细胞机制并开发保护 BBS 患者视力的治疗干预措施。我们之前的研究确定外节（OS）中蛋白质的积累可能是光感受器的主要原因 BBS 中的变性，代表了光感受器变性的一种新机制。在接下来的时间里在资助周期中，我们将探索操作系统中的蛋白质积累如何诱导光感受器变性。我们的初步数据表明，Stx3（一种 SNARE 蛋白，促进膜融合事件）和蛋白酶体超载应激都参与其中。拟议的研究将确定这些因素如何导致 BBS 中的光感受器变性。这项研究的结果将极大地增进我们对纤毛相关视网膜病变的理解，并提供重要的信息为基于机制的疗法的发展奠定了基础。