Formation and New Components of the Usher 2 Protein Complex in Photoreceptors

光感受器中 Usher 2 蛋白复合物的形成和新成分

基本信息

批准号：
8655877
负责人：
Jun Yang
金额：
$ 32.85万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655877
关键词：
Actins Address Affect Affinity Antibodies Binding Biochemical Biological Assay Biological Process Blindness Bundling Cell Aggregation Cell Culture Techniques Cell Death Cell physiology Cellular Assay Cellular biology Co-Immunoprecipitations Complex Cultured Cells Cytoskeleton Defect Disease Foundations Future Genes Goals Hair Cells In Vitro Individual Kinetics Knockout Mice Knowledge Lead Leber&apos s disease Light Literature Mediating Membrane Molecular Mus Mutant Strains Mice Phosphotransferases Photoreceptors Play Positioning Attribute Protein Fragment Protein-Serine-Threonine Kinases Proteins Reagent Recombinant Proteins Research Retina Retinal Retinal Degeneration Role Scaffolding Protein Series Signal Pathway Signal Transduction Solid Surface Plasmon Resonance System Techniques Testing Therapeutic Tissues United States Usher Syndrome Usher Syndrome, Type 2A VLGR1 gene WHRN gene Work Yeasts effective therapy extracellular hearing impairment in vivo insight interest novel protein complex public health relevance therapeutic development yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Usher syndrome is the most common condition with vision and hearing loss. There is no cure for this disease. Our long-term goal is to understand the molecular mechanisms of retinal degeneration in Usher syndrome, which will lay a solid foundation for developing effective therapies for this disease. The main focus of this proposal is the formation and new components of the protein complex composed of USH2A, VLGR1 and WHRN in photoreceptors. The genes encoding these three proteins are the causative genes for Usher syndrome type 2, the most common form of Usher syndrome. Our recent research has demonstrated that the Usher 2 protein complex is located at the periciliary membrane complex (PMC) in mammalian photoreceptors. Defects in this protein complex cause ultra structural abnormalities surrounding the PMC and eventually lead to photoreceptor cell death. However, the formation, composition and biological function of this complex are largely not clear. The central HYPOTHESIS of this study is that WHRN, as a scaffold protein, associates with USH2A, VLGR1 and other components of the Usher 2 protein complex, and that these components contribute to the function of the whole complex in photoreceptors. To test this hypothesis, two specific aims will be addressed. In specific aim 1, interactions among USH2A, VLGR1 and WHRN will be thoroughly studied using a series of biochemical assays in both in vitro and in vivo systems. The possibility of the existence of a ternary complex will be explored. In specific aim 2, two newly identified candidate components of the Usher 2 protein complex will be studied in photoreceptors. The functional significance of these new components in this complex will be further analyzed using their mutant mice. This study will generate new insight into the function of the Usher 2 protein complex in photoreceptors, which may be applied in hair cells as well. Therefore, this study will help fill the gap in our knowledge about the mechanisms underlying retinal degeneration and, perhaps, hearing impairment in Usher syndrome, which might be valuable for the future development of therapeutic strategies for Usher syndrome. Furthermore, this study will provide a better understanding of the role of the PMC in photoreceptor cell biology.

描述（由申请人提供）：亚瑟综合症是最常见的视力和听力损失疾病。这种疾病无法治愈。我们的长期目标是了解Usher综合征视网膜变性的分子机制，这将为开发针对该疾病的有效疗法奠定坚实的基础。该提案的主要关注点是光感受器中由USH2A、VLGR1和WHRN组成的蛋白质复合物的形成和新成分。编码这三种蛋白质的基因是亚瑟综合症 2 型（亚瑟综合症最常见的形式）的致病基因。我们最近的研究表明，Usher 2 蛋白复合物位于哺乳动物光感受器的纤毛周膜复合物 (PMC) 处。这种蛋白质复合物的缺陷会导致 PMC 周围的超微结构异常，并最终导致感光细胞死亡。然而，该复合物的形成、组成和生物学功能很大程度上尚不清楚。这项研究的中心假设是，WHRN 作为支架蛋白，与 USH2A、VLGR1 和 Usher 2 蛋白复合物的其他成分相关，并且这些成分有助于光感受器中整个复合物的功能。为了检验这一假设，将解决两个具体目标。在具体目标 1 中，将在体外和体内系统中使用一系列生化测定来彻底研究 USH2A、VLGR1 和 WHRN 之间的相互作用。将探讨三元配合物存在的可能性。在具体目标 2 中，将在光感受器中研究 Usher 2 蛋白复合物的两个新鉴定的候选成分。该复合物中这些新成分的功能意义将使用其突变小鼠进行进一步分析。这项研究将对 Usher 2 蛋白复合物在光感受器中的功能产生新的见解，这也可能应用于毛细胞。因此，这项研究将有助于填补我们对亚瑟综合征视网膜变性和听力损伤机制的认识空白，这对于亚瑟综合征治疗策略的未来发展可能有价值。此外，这项研究将有助于更好地理解 PMC 在感光细胞生物学中的作用。