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：
8450915
负责人：
QING Y ZHENG
金额：
$ 30.37万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450915
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 abstracting 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

Project Summary/Abstract 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.

项目摘要/摘要 Usher综合征（USH）是一种以先天性为特征的临床和遗传异质性疾病耳聋和色素性视网膜炎。这是伴有失明的最常见原因。头发细胞置换或再生疗法并未真正解决耳朵疾病的耳聋问题。一个替代替换失去毛细胞的替代方法是防止其损失，这是一个特别有前途的调查线。许多USH患者将受益于人工耳蜗，但保存螺旋神经节细胞对于人工耳蜗的成功很重要，因为需要最小的螺旋神经节细胞密度用于有效的人工耳蜗。耳蜗中存在的残留毛细胞可以促进螺旋的生存神经神经元通过神经营养物质的释放。因此，发现了治疗靶标的防止毛细胞死亡是帮助1名患者应对人工耳蜗和其他的关键治疗方案成功。鼠标模型促进实验确定各种的功能涉及usher病的基因。我们已经开发了usher综合征的鼠标模型。因此，我们建议以下具体目的：1）确定并表征新的鼠标耳聋模型的突变（用于 Usher 1综合征和长期综合症），为评估药物治疗提供了理想的时间窗口； 2）确定导致毛细胞死亡和听力丧失模型的关键分子和机制 Usher 1综合征； 3）证明遗传听力丧失和毛细胞死亡的概念可以通过 Otoprotection疗法。拟议的研究结果将使人类健康受益。