Deciphering the Usher I protein interactome using a genetic approach

使用遗传方法破译 Usher I 蛋白相互作用组

基本信息

批准号：
7789473
负责人：
QING Y ZHENG
金额：
$ 33.03万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7789473
关键词：
Accounting Affect Alleles Apoptosis Apoptotic Auditory Biological Preservation Blindness Caspase Inhibitor Cell Death Characteristics Chromosome Mapping Cochlea Cochlear Implants Collection Data Development Dexamethasone Diagnosis Disease Ear Ear Diseases Event Gene Proteins Genes Genetic Genetic Complementation Test Genetic Models Genetic Transcription Genomics Hair Hair Cells Health Hearing Impaired Persons Hearing problem Hereditary Disease Human In Vitro Individual Inner Hair Cells Investigation Labyrinth Lead Learning Lesion Link Mediator of activation protein Modeling Molecular Molecular Genetics Mus Mutant Strains Mice Mutate Mutation Natural regeneration Neurons Outcome Outer Hair Cells Pathology Pathway interactions Patients Pharmacotherapy Phenotype Play Population Presbycusis Prevention Proteins Proteomics Research Residual state Retinitis Pigmentosa Role Stereocilium Syndrome Testing Therapeutic Time Usher Syndrome Work alanylaspartic acid blind congenital deafness deafness density early onset effective therapy ganglion cell hearing impairment inhibitor/antagonist mouse model mutant mutant mouse model novel positional cloning prevent research study spiral ganglion success therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The Usher Syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by congenital deafness and retinitis pigmentosa. It is the most common cause of deafness accompanied by blindness. Hair cell replacement or regeneration therapies have not really solved the deafness problem of ear diseases. An alternative to replacing lost hair cells is to prevent their loss in the first place, which is a particularly promising line of investigation. Many USH patients will benefit from cochlear implants, but preservation of spiral ganglion cells is important for success of cochlear implants because a minimal density of spiral ganglion cells is required for effective cochlear implants. Residual hair cells present in the cochlea could promote the survival of spiral ganglion neurons by release of neurotrophic substances. Therefore, discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. Mouse models facilitate experiments to determine the function of the various genes involved in Usher disease. We have developed mouse models for Usher syndrome. Thus, we propose the following specific aims: 1) identify the mutation in and characterize a new mouse deafness model (for Usher 1 syndrome and presbycusis) that provides an ideal window of time for evaluating drug therapy; 2) identify key molecules and mechanisms that lead to hair cell death and hearing loss in the models for the Usher 1 syndrome; 3) prove the concept that genetic hearing loss and hair cell death can be prevented by otoprotection therapy. Results of the proposed research will benefit human health. Usher Syndrome (USH) accounts for 6% of the congenitally deaf population and more than 50% of the deaf-blind population. Discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. We propose to develop a new mouse deafness model, a model for Usher 1 syndrome and presbycusis, which has an ideal window of time for evaluating drug therapy.

描述（由申请人提供）：Usher综合征（USH）是一种以先天性耳聋和色素性视网膜炎为特征的临床和遗传异质性疾病。这是伴有失明的最常见原因。毛细胞的替代或再生疗法并未真正解决耳朵疾病的耳聋问题。替代丢失毛细胞的一种替代方法是首先防止它们的损失，这是一项特别有希望的调查。许多USH患者将受益于人工耳蜗，但是螺旋神经节细胞的保存对于成功的人工耳蜗很重要，因为有效的耳蜗植入物需要最小的螺旋神经节细胞密度。耳蜗中存在的残留毛细胞可以通过释放神经营养物质来促进螺旋神经节神经元的存活。因此，发现预防毛细胞死亡的治疗靶标是帮助1名患者成功应对人工耳蜗和其他治疗方案的关键。小鼠模型促进了实验，以确定usher疾病中涉及的各种基因的功能。我们已经开发了usher综合征的鼠标模型。因此，我们提出以下特定目的：1）确定并表征新的小鼠耳聋模型（对于Usher 1综合征和长期），该模型为评估药物治疗提供了理想的时间窗口； 2）确定导致毛细细胞死亡和听力损失的关键分子和机制。 3）证明了遗传性听力损失和毛细胞死亡可以通过探测治疗预防的概念。拟议的研究结果将使人类健康受益。 Usher综合征（USH）占先天性聋哑人群的6％，占聋哑人群的50％以上。发现预防毛细胞死亡的治疗靶标是帮助1名患者成功应对人工耳蜗和其他治疗方案的关键。我们建议开发一种新的小鼠耳聋模型，这是Usher 1综合征和老同学的模型，该模型具有评估药物治疗的理想时间窗口。