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: 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
• 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

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.

摘要 突变破坏睫状体组装和运输是遗传性视网膜病变的常见原因。 退化，导致早期严重失明。Bardet-Biedl综合征（BBS）是人类的一种 与有缺陷的纤毛运输和光感受器变性相关的遗传疾病。然而，在这方面， BBS中光感受器变性的病理机制的细节在很大程度上是未知的， 尚未开发出有效的治疗方案。这项研究计划的长期目标是 阐明BBS感光细胞变性的分子和细胞机制， 治疗干预，以保持BBS患者的视力。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 在BBS中的退化，代表感光细胞退化的新机制。在下一个 格兰特周期，我们将探讨如何在OS蛋白质积累诱导感光细胞变性。我们 初步数据表明，Stx 3（一种SNARE蛋白，其促进 膜融合事件）和蛋白酶体过载应激。拟定的研究将 确定这些因素如何导致BBS中的感光细胞变性。本研究的结果 将大大推进我们对纤毛相关视网膜病变的理解，并提供重要的 为机制疗法的发展奠定了基础。