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：
8249030
负责人：
Jun Yang
金额：
$ 33.64万
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/8249030
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 Degenerative Disorder 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 Work Yeasts effective therapy extracellular hearing impairment in vivo insight interest novel protein complex public health relevance therapeutic development yeast two hybrid system

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 Degenerative Disorder 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 Work Yeasts effective therapy extracellular hearing impairment in vivo insight interest novel protein complex public health relevance therapeutic development yeast two hybrid system

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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. PUBLIC HEALTH RELEVANCE: Defects in the Usher 2 multi-protein complex cause Usher syndrome type 2, a condition with both retinitis pigmentosa and congenital hearing impairment. This proposal is to investigate the formation of this complex and its potential new components. Completion of this work is expected to provide more complete insight into the biological function of this complex and the disease mechanism underlying Usher syndrome.

描述（由申请人提供）：Usher综合征是视力和听力损失的最常见状况。无法治愈这种疾病。我们的长期目标是了解Usher综合征视网膜变性的分子机制，这将为为该疾病开发有效疗法奠定坚实的基础。该建议的主要重点是光感受器中由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Usher综合征2型的致病基因，这是Usher综合征的最常见形式。我们最近的研究表明，Usher 2蛋白质复合物位于哺乳动物感受器中的周围膜复合物（PMC）。该蛋白质复合物的缺陷会导致PMC周围的超结构异常，并最终导致感光细胞死亡。但是，这种复合物的形成，组成和生物学功能在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蛋白质复合物的其他成分相关，并且这些成分在光感受器中有助于整个复合物的功能。为了检验这一假设，将解决两个具体目标。在特定的目标1中，将使用一系列在体外和体内系统中的生化测定法对USH2A，VLGR1和WHRN之间的相互作用进行彻底研究。将探索存在三元络合物的可能性。在特定的目标2中，将在感光体中研究Usher 2蛋白复合物的两个新鉴定的候选成分。这些新组件在该复合物中的功能意义将使用其突变小鼠进一步分析。这项研究将对感光体中的Usher 2蛋白复合物的功能产生新的见解，这些蛋白质复合物也可以应用于毛细胞中。因此，这项研究将有助于填补我们对视网膜变性的机制的了解，并可能在Usher综合征中听力障碍，这对于未来的Usher综合征治疗策略可能很有价值。此外，这项研究将更好地了解PMC在感光细胞生物学中的作用。公共卫生相关性：USHER 2多蛋白复合物的缺陷导致Usher综合征2型，这种疾病既有色素性视网膜炎和先天性听力障碍。该建议是研究该复合物及其潜在的新组成部分的形成。预计这项工作的完成将为这种复合物的生物学功能和usher综合征的疾病机制提供更完整的见解。