Molecular Mechanisms of Connecting Cilium Function in the Vertebrate Eye

脊椎动物眼睛纤毛功能连接的分子机制

• 批准号: 10163942
• 负责人: Graeme Mardon
• 金额: $ 19.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163942
• 关键词: Adult; Affect; Alleles; Architecture; Bacterial Artificial Chromosomes; Biological Assay; Biology; Blindness; Child; Cilia; Co-Immunoprecipitations; Complex; Defect; Dependence; Diagnosis; Disease; Evaluation; Eye; Genes; Genetic; Goals; Human; Inherited; Lead; Link; Maintenance; Maps; Mediating; Microscopy; Modeling; Molecular; Mus; Names; Nephronophthisis; Optics; Orthologous Gene; Pathogenesis; Pathology; Phenotype; Photoreceptors; Play; Proteins; RPGR gene; Regulation; Resolution; Retina; Retinal Diseases; Role; Signal Transduction; Structural Protein; Structural defect; Structure; Syndrome; Tamoxifen; Tertiary Protein Structure; Testing; Vertebrate Photoreceptors; base; ciliopathy; experimental study; gain of function; genetic testing; human disease; improved; in vivo; in vivo evaluation; insight; kinetosome; member; mutant; mutant mouse model; novel; personalized medicine; protein complex; protein protein interaction; protein transport; reconstruction; scaffold; synergism; trafficking; young adult

Project Summary The long-term goal of this project is to improve our understanding of the molecular mechanisms of inherited retinal diseases (IRDs) and to develop personalized treatments. Strikingly, ciliopathies have been identified as one of the major causes of IRDs with 25% of the known disease-causing genes involved in proper cilia formation and function in photoreceptor cells. However, despite the large number of retinal disease genes related to cilium function, the precise disease mechanisms remain largely unknown. We have recently discovered a novel subdomain of the photoreceptor connecting cilium (CC), named the photoreceptor- specific transition zone (PSTZ), which plays a critical role in CC stability and function. Establishment of the PSTZ depends on Spata7, a known LCA disease gene, and other members of the RPGR complex. In this proposal, we plan to utilize Spata7 as an entry point to better understand the function of this novel structure in the connecting cilium of photoreceptor cells. Our Specific Aims are to: Specific Aim 1: Investigate the mechanism of PSTZ establishment Specific Aim 2: Determine the role of RPGR complex members in PSTZ structure and function Specific Aim 3: Determine the role of Spata7 in RPGR complex assembly and in establishment versus maintenance of CC structure and function Together these studies will provide a systematic evaluation of the PSTZ structure, key protein composition, regulation, and function, thereby providing novel insights concerning the molecular mechanisms of protein trafficking through the connecting cilium of photoreceptor cells. Given the central role primary cilia play not only in retinal disease, but also many other syndromic pathologies, these aims have the potential to make a high impact in our understanding of and ability to diagnose and treat human disease.

项目总结