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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(申请人提供)：引座症是最常见的视力和听力损失的症状。这种疾病没有治愈的办法。我们的长期目标是了解Usher综合征视网膜变性的分子机制，为开发有效的治疗方法奠定坚实的基础。这一建议的主要焦点是光感受器中由USH2A、VLGR1和WHRN组成的蛋白质复合体的形成和新的成分。编码这三种蛋白的基因是亚瑟综合征2型的致病基因，亚瑟综合征是亚瑟综合征最常见的形式。我们最近的研究表明，Usher-2蛋白复合体位于哺乳动物光感受器的睫状膜复合体(PMC)。这种蛋白质复合体的缺陷会导致PMC周围的超微结构异常，最终导致光感受器细胞死亡。然而，该复合体的形成、组成和生物学功能在很大程度上尚不清楚。本研究的中心假设是，WHRN作为一种支架蛋白，与USH2A、VLGR1和Usher 2蛋白复合体的其他成分相关联，这些成分参与了光感受器中整个复合体的功能。为了验证这一假设，我们将提出两个具体目标。在具体目标1中，将使用一系列生化分析方法在体外和体内系统中深入研究USH2A、VLGR1和WHRN之间的相互作用。我们将探讨三元络合物存在的可能性。在具体目标2中，将研究光感受器中新发现的Usher 2蛋白复合体的两个候选成分。这些新成分在这个复合体中的功能意义将通过它们的突变小鼠来进一步分析。这项研究将对光感受器中Usher 2蛋白复合体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Usher综合征视网膜变性甚至听力障碍的机制的认识空白，这可能对未来Usher综合征的治疗策略的制定有价值。此外，本研究还将对PMC在光感受器细胞生物学中的作用提供更好的理解。