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: 10172910
• 负责人: Graeme Mardon
• 金额: $ 46.01万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172910
• 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.

项目摘要 该项目的长期目标是提高我们对遗传性疾病的分子机制的理解。 视网膜疾病（IRD），并开发个性化治疗。引人注目的是，纤毛病变已经被确定为 作为IRD的主要原因之一，25%的已知致病基因涉及固有纤毛 感光细胞的形成和功能。然而，尽管有大量的视网膜疾病基因， 与纤毛功能有关，精确的疾病机制在很大程度上仍然未知。我们最近 发现了一个新的亚结构域的光感受器连接纤毛（CC），命名为光感受器- 特定的过渡区（PSTZ），在CC的稳定性和功能中起着关键作用。成立 PSTZ依赖于已知的LCA疾病基因Spata 7和RPGR复合物的其他成员。在这 我们计划利用Spata 7作为切入点，以更好地了解这种新型结构的功能 在感光细胞的连接纤毛中。我们的具体目标是： 具体目标1：研究PSTZ的建立机制 具体目标2：确定RPGR复合物成员在PSTZ结构和功能中的作用 具体目标3：确定Spata 7在RPGR复合物组装中的作用以及在 社区中心结构和职能建立与维持 这些研究将为PSTZ结构、关键蛋白质组成 调节和功能，从而提供有关蛋白质的分子机制的新见解， 通过感光细胞的连接纤毛进行运输。由于初级纤毛的中心作用， 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 对我们诊断和治疗人类疾病的理解和能力有很大的影响。

项目成果

Corrigendum to "Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice" [Exp. Eye Res. 166 (2018) 120-130].

“光感受器中 Spata7 的条件性缺失导致小鼠进行性视网膜变性”的勘误表 [实验。

• DOI: 10.1016/j.exer.2018.03.011
• 发表时间: 2018
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Eblimit,A;Agrawal,SA;Thomas,K;Anastassov,IA;Abulikemu,T;Moayedi,Y;Mardon,G;Chen,R
• 通讯作者: Chen,R