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: 9499797
• 负责人: Graeme Mardon
• 金额: $ 47.44万
• 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/9499797
• 关键词: Adult; Affect; Alleles; Architecture; Biological Assay; Biology; Blindness; Carrier Proteins; Child; Cilia; Co-Immunoprecipitations; Complex; Defect; Dependence; Diagnosis; Disease; Evaluation; Eye; Genes; Genetic; Genetic screening method; 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; 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; 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.

项目概要 该项目的长期目标是提高我们对遗传性分子机制的理解 视网膜疾病（IRD）并开发个性化治疗。引人注目的是，纤毛病已被发现 作为 IRD 的主要原因之一，25% 的已知致病基因与纤毛有关 感光细胞的形成和功能。然而，尽管存在大量视网膜疾病基因 与纤毛功能相关，确切的疾病机制仍然很大程度上未知。我们最近有 发现了连接纤毛（CC）的光感受器的一个新的子域，命名为光感受器- 特定过渡区 (PSTZ)，在 CC 稳定性和功能中起着至关重要的作用。成立 PSTZ 依赖于 Spata7（一种已知的 LCA 疾病基因）和 RPGR 复合体的其他成员。在这个 提案中，我们计划利用 Spata7 作为切入点来更好地理解这种新颖结构的功能 在感光细胞的连接纤毛中。我们的具体目标是： 具体目标1：探讨PSTZ建立机制 具体目标 2：确定 RPGR 复合体成员在 PSTZ 结构和功能中的作用 具体目标 3：确定 Spata7 在 RPGR 复合体组装和 CC结构和功能的建立与维护 这些研究将共同​​对 PSTZ 结构、关键蛋白质组成、 调节和功能，从而提供有关蛋白质分子机制的新见解 通过感光细胞的连接纤毛进行运输。鉴于初级纤毛发挥的核心作用并不 不仅在视网膜疾病中，而且在许多其他综合征病理中，这些目标有可能使 对我们理解和诊断和治疗人类疾病的能力产生重大影响。