The functions of PDZ domain scaffold proteins in Usher syndrome

PDZ结构域支架蛋白在Usher综合征中的功能

基本信息

批准号：
8301725
负责人：
Monte Westerfield
金额：
$ 29.21万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-29 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301725
关键词：
Affect American Antibodies Behavior Binding Biological Assay Blindness Cell Death Cells Cilia Complex Counseling Defect Development Diagnosis Disease Distal Ear Electron Microscopy Electroretinography Equilibrium Eye Gene Family Genes Genetic Genetic Counseling Hair Cells Hearing Hearing Impaired Persons Human In Vitro Kinocilium Labyrinth Lead Link Maintenance Modeling Mutant Strains Mice Mutation Opsin Organ Orthologous Gene Patients Phenotype Photoreceptors Phototransduction Play Process Proteins Research Retina Retinal Retinal Degeneration Retinitis Pigmentosa Role Scaffolding Protein Sensory Hair Site Stereocilium Symptoms Synapses Testing Transgenic Organisms Tubulin Usher Syndrome Visual Work Zebrafish assay development congenital deafness deafness gain of function gene discovery human disease light microscopy member mutant protein complex protein function public health relevance research study scaffold synaptic function therapy design trafficking

项目摘要

DESCRIPTION (provided by applicant): Human Usher syndrome, the most frequent cause of deaf blindness, is characterized by congenital deafness, due to loss of sensory hair cells, and progressive retinal degeneration, due to retinitis pigmentosa. Twelve different chromosomal loci have been linked to Usher syndrome and nine of the genes have been identified to date. Identification of the missing Usher genes is crucial for diagnosis and patient counseling. The nine known genes encode a surprisingly broad range of different types of proteins. Although the roles of these proteins are poorly understood, recent studies suggest that they function together in a multimolecular complex. This project focuses on analysis of the two scaffold proteins that play a central role in organizing the complex, and a new potential member of this organizing scaffold. The project has three main aims: 1) to determine whether the newly discovered gene encodes an Usher scaffold protein, 2) to analyze the functions of the scaffold proteins in organizing the Usher proteins into a complex, and 3) to determine how the Usher protein complex functions in cells of the inner ear and retina. PUBLIC HEALTH RELEVANCE: Usher syndrome, the leading cause of deaf blindness, is a genetically heritable disorder that affects tens of thousands of Americans. Deafness in Usher syndrome is due to loss of inner ear sensory hair cells and can range from moderate to profound. Blindness is due to retinitis pigmentosa. Mutations in any one of at least a dozen different genes can cause Usher syndrome, only nine of the genes have been identified. Recent research suggests that the various proteins encoded by the Usher genes act together in a multimolecular complex, although the processes that lead to loss of inner ear and retinal cells when the complex is defective are unknown. This project will elucidate how and where the complex functions and the mechanisms by which it assembles. The project will also identify new members of the Usher gene family. This information is important for diagnosis, genetic counseling, and design of therapies for Usher patients.

描述（由申请人提供）：人类亚瑟综合症是耳聋失明的最常见原因，其特征是由于感觉毛细胞丧失而导致的先天性耳聋，以及由于视网膜色素变性而导致的进行性视网膜变性。十二个不同的染色体位点与亚瑟综合症有关，迄今为止已鉴定出其中九个基因。鉴定缺失的 Usher 基因对于诊断和患者咨询至关重要。这九个已知基因编码令人惊讶的广泛不同类型的蛋白质。尽管人们对这些蛋白质的作用知之甚少，但最近的研究表明它们在多分子复合物中共同发挥作用。该项目重点分析在组织复合物中起核心作用的两种支架蛋白，以及该组织支架的新的潜在成员。该项目有三个主要目标：1) 确定新发现的基因是否编码 Usher 支架蛋白，2) 分析支架蛋白在将 Usher 蛋白组织成复合物时的功能，以及 3) 确定 Usher 蛋白如何内耳和视网膜细胞的复杂功能。公共卫生相关性：亚瑟综合症是导致聋哑人失明的主要原因，是一种影响数以万计的美国人的遗传性疾病。亚瑟综合症中的耳聋是由于内耳感觉毛细胞的丧失造成的，耳聋程度可以从中度到重度不等。失明是由于视网膜色素变性引起的。至少十几种不同基因中的任何一种突变都可能导致亚瑟综合症，但目前仅鉴定出其中九种基因。最近的研究表明，由 Usher 基因编码的各种蛋白质在多分子复合物中共同作用，尽管当该复合物有缺陷时导致内耳和视网膜细胞损失的过程尚不清楚。该项目将阐明复杂功能的方式和地点以及其组装机制。该项目还将鉴定 Usher 基因家族的新成员。这些信息对于 Usher 患者的诊断、遗传咨询和治疗设计非常重要。