Drug discovery for hair cell regeneration in adult mammalian cochleae

成年哺乳动物耳蜗毛细胞再生的药物发现

基本信息

批准号：
8682710
负责人：
JIAN ZUO
金额：
$ 21.88万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8682710
关键词：
Adult Affect Aftercare Age Age-Months Auditory Biological Assay Cell Line Cell Survival Cells Clinical Trials Cochlea Dose Ectopic Expression Exhibits FDA approved Genes Genetic Transcription Hair Cells Hearing Hela Cells Histologic Hour Human Human Cell Line Individual Inhibitory Concentration 50 Injection of therapeutic agent Injury Labyrinth Lead Luciferases Mammals Measures Messenger RNA Mus Natural regeneration Neonatal Noise Pharmaceutical Preparations Population Recovery Regulatory Pathway Sensory Supporting Cell Tamoxifen Testing Transgenic Mice Wild Type Mouse antineoplastic antibiotics drug development drug discovery gamma secretase hair cell regeneration hearing impairment high throughput screening in vivo inhibitor/antagonist intraperitoneal mouse model pre-clinical preclinical safety promoter public health relevance safety study small molecule

项目摘要

DESCRIPTION (provided by applicant): Hearing is impaired in more than 10% of the human population. Despite significant progress in neonatal regeneration of mammalian cochlear hair cells (HCs), such regeneration in adults has proved extremely difficult. While gamma secretase inhibitors have shown some promise in regenerating noise-damaged auditory HCs in adult mice, no drugs have been proven effective for auditory HC regeneration in adult humans. Interestingly, we recently demonstrated that supporting cells (which surround hair cells) can be converted to HCs in mature cochleae through combined manipulation of two key genes, one of which (p27Kip1 or p27) is inactivated and one of which (Atoh1) is activated. These findings led us to screen for small-molecule inhibitors of p27 and to characterize them in cell lines. We propose to test the inhibitory effects of these lead compounds in cochlear explants and in vivo in adult wild-type and transgenic mice, with or without noise damage. These exploratory studies will provide the key "proof of concept" for using small-molecule inhibitors of p27, together with small-molecule activators of Atoh1, to regenerate damaged auditory HCs in adult mammals. The final lead compounds identified here will advance to the drug development pipeline for optimization, selection, and preclinical safety analysis, and eventually to clinical trials for HC regeneration in humans. These studies may lead to a breakthrough in the treatment of hearing loss caused by noise, antibiotics, chemotherapy, or age.

描述（由申请人提供）：超过 10% 的人口存在听力障碍。尽管哺乳动物耳蜗毛细胞（HC）的新生儿再生取得了重大进展，但成人的这种再生已被证明极其困难。虽然 γ 分泌酶抑制剂在成年小鼠中再生受噪声损伤的听觉 HC 方面显示出一定的前景，但没有药物被证明对成年人的听觉 HC 再生有效。有趣的是，我们最近证明，通过两个关键基因的联合操作，支持细胞（围绕毛细胞）可以在成熟耳蜗中转化为 HC，其中一个（p27Kip1 或 p27）失活，其中一个（Atoh1）激活。这些发现促使我们筛选 p27 小分子抑制剂并在细胞系中表征它们。我们建议在有或没有噪音损伤的成年野生型和转基因小鼠的耳蜗外植体和体内测试这些先导化合物的抑制作用。这些探索性研究将为使用 p27 小分子抑制剂和 Atoh1 小分子激活剂来再生成年哺乳动物受损的听觉 HC 提供关键的“概念证明”。这里确定的最终先导化合物将进入药物开发流程，进行优化、选择和临床前安全性分析，并最终进入人体 HC 再生的临床试验。这些研究可能会为由噪音、抗生素、化疗或年龄引起的听力损失的治疗带来突破。