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