A Novel Model System for Restoring Hearing in vivo

一种恢复体内听力的新型模型系统

基本信息

批准号：
10058225
负责人：
Todd P Coleman
金额：
$ 28.55万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058225
关键词：
Actins Acute Address Adult Affect Age Aging Biological Models Birth Brain Child Childhood Climacteric Cochlear Hearing Loss Cochlear Implants Development Disease Doxycycline Ear Exhibits Future Gene Expression Gene Expression Regulation Genes Genetic Hair Cells Hearing Hearing Aids Hearing Tests Human Intestines Knock-out Knockout Mice Labyrinth Length Light Luciferases Maintenance Mechanics Methods Mus Mutation Neonatal Newborn Infant Organ of Corti Organism Photophobia Physiological Proteins Repression Resolution Role Sensory Hair Signal Transduction Structure Switch Genes System Testing Tetanus Helper Peptide Therapeutic Studies Tissue Extracts Tissues Transgenes Transgenic Mice Viral Viral Vector Wild Type Mouse Work base congenital deafness critical period deaf deafness experimental study gene induction gene therapy genetic regulatory protein hearing impairment hearing loss treatment hearing restoration hereditary hearing loss high resolution imaging imaging approach improved in vivo innovation insight interest mouse model normal hearing novel phyA phytochrome phyB phytochrome postnatal promoter restoration sound spatiotemporal tectorial membrane therapy duration tool transduction efficiency transgene expression

项目摘要

Project Summary/Abstract Approximately 1 out of 400 children are born with significant hearing loss, making congenital deafness one of the most common disorders affecting young children. Approximately 50% of congenital deafness is genetic in origin. Currently, the only available treatments for hearing loss are cochlear implants or hearing amplification. While these treatments are often life-changing, they are limited in their ability to restore hearing to normal, which results in lifelong struggles beginning acutely in childhood. Gene therapy approaches for treating recessive hearing loss presents a challenging but exciting opportunity. Viral delivery of functional genes to the ear is challenging, especially in mice – current in vivo viral delivery methods only transduce a fraction of the sensory hair cells necessary for proper hearing function, and only works easily for smaller proteins. Moreover, multiple applications of viral vectors may be required to target the optimal timing and duration for therapy. Mice and humans lacking the actin-regulatory protein Eps8 are deaf, and Eps8 KO mice have very short stereocilia that fail to contact the tectorial membrane in the organ of Corti. A novel transgenic mouse line will be generated to study the potential of postnatal gene expression in a deaf Eps8 KO mouse model. Using the PhyB system, a mouse line will be created wherein any UAS controlled transgene’s expression can be activated with red light or inactivated with far-red light. Using this system, UAS-Eps8 expression in vivo will be induced by either red light or doxycycline. Systematically varying the initiation and duration of Eps8 expression, then testing for hearing function and stereocilia elongation will facilitate the restoration potential of stereocilia elongation and hearing restoration in vivo in postnatal mice. Furthermore, the role of Eps8 in both development and maintenance of stereocilia over the lifetime of the organism will be elucidated in future studies. Overall, this proposal will pave the way for many future projects probing the effects of gene expression modulation in vivo and will provide an innovative but practical model system for probing and expanding the critical period for hearing restoration.

项目概要/摘要大约每 400 名儿童中就有 1 名出生时患有严重听力损失，这使得先天性耳聋成为其中之一影响幼儿的最常见疾病，大约 50% 的先天性耳聋是遗传性的。目前，治疗听力损失的唯一方法是人工耳蜗或听力放大。虽然这些治疗通常可以改变生活，但它们恢复正常听力的能力有限，这导致从童年开始就开始与基因治疗方法进行终生斗争。隐性听力损失提供了一个具有挑战性但令人兴奋的机会。耳朵是具有挑战性的，特别是在小鼠中——目前的体内病毒传递方法只能转导一小部分感觉毛细胞是正常听力功能所必需的，并且只对较小的蛋白质起作用。可能需要多次应用病毒载体来确定小鼠的最佳治疗时机和持续时间。缺乏肌动蛋白调节蛋白 Eps8 的人类是聋子，而 Eps8 KO 小鼠的静纤毛非常短无法接触柯蒂氏器盖膜的新型转基因小鼠系。生成用于研究耳聋 Eps8 KO 小鼠模型中出生后基因表达的潜力。 PhyB系统，将创建一个小鼠品系，因此任何UAS控制的转基因表达都可以使用该系统，用红光激活或用远红光灭活，UAS-Eps8在体内表达。由红光或多西环素诱导，系统地改变 Eps8 表达的起始和持续时间，然后测试听力功能和静纤毛伸长率将有助于静纤毛的恢复潜力出生后小鼠体内伸长和听力恢复。此外，Eps8 在这两种发育中的作用总体而言，在生物体的整个生命周期中静纤毛的维持将在未来的研究中得到阐明。该提案将为许多未来探索基因表达调节影响的项目铺平道路 vivo将为探索和拓展关键期提供一个创新但实用的模型系统听力恢复。