Epigenetic mechanisms underlying the failure of hair cell regeneration in mammals

哺乳动物毛细胞再生失败的表观遗传机制

基本信息

批准号：
10200749
负责人：
ANDREW P. MCMAHON
金额：
$ 58.16万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200749
关键词：
ATAC-seq Acetylation Adult Birth Cell Death Cell Differentiation process Cell Nucleus Cells ChIP-seq Chromatin Chromatin Structure Cochlea Complex Data Deacetylation Dependence Developmental Gene Embryo Epigenetic Process Excision Failure Future Gene Activation Gene Silencing Genes Genetic Transcription Goals Hair Cells Heterochromatin Histone H3 Individual Inner Supporting Cell Labyrinth Lateral Lysine Mammals Mediating Methods Modeling Modification Molecular Mus Natural regeneration Newborn Infant Nucleosomes Organ of Corti Perinatal Pharmacology Physical condensation Polycomb Population Regenerative Medicine Regenerative capacity Role Sensory Hair Structure Supporting Cell Techniques Technology Testing Up-Regulation Work age related deaf disability epigenetic silencing epigenome genome-wide hair cell regeneration hearing impairment hearing restoration inhibitor/antagonist knockout gene notch protein perinatal period permanent hearing loss postnatal programs regeneration potential transcription factor transcriptome transcriptome sequencing transdifferentiation

项目摘要

Project Summary/Abstract: Sensory hair cell regeneration does not occur spontaneously in the mature mammalian organ of Corti, making hearing loss permanent. The goal of this proposal is to identify the causes and mechanisms behind the failure of hair cell regeneration, as well as ways to stimulate regeneration in surviving populations of inner ear supporting cells in deafened individuals. Our primary hypothesis is that regeneration requires the re- engagement of developmental gene networks to guide supporting cells to a hair cell fate, and that during postnatal inner ear maturation, epigenetic barriers arise that block the re-activation of these gene networks. The goal is to develop methods to overcome these epigenetic barriers, and to establish new cell fates with regenerative potential within the organ of Corti. Experimentally, perinatal mice retain a latent capacity for direct supporting cell transdifferentiation to a hair cell-like fate, but this capacity is rapidly lost in the first weeks after birth. This age-dependent change in regenerative potential provides a window through which to investigate the transition from a permissive to a non-permissive state for this form of regeneration in the normally maturing organ of Corti. The work of this proposal is to elucidate the mechanism(s) of epigenetic control of transdifferentiation in perinatal supporting cells (Aim1) and to identify the machinery of maturation-related changes in epigenetic/chromatin structure in supporting cells of the inner ear. (Aim 2). We hypothesize that these changes are responsible for the failure of regeneration. Finally, to investigate the epigenetic structure of adult supporting cell chromatin in normal and deafened mice (Aim 3). We hypothesize that manipulation of the epigenetic state is an important approach for future regenerative medicine approaches to restoring lost hair cells.

项目摘要/摘要：感觉毛细胞再生不会自发地发生在Corti的成熟哺乳动物器官中，使听力损失永久性。该提议的目的是确定背后的原因和机制毛细胞再生的失败以及刺激内耳尚存种群再生的方法支持聋人的细胞。我们的主要假设是再生需要重新发育基因网络的参与以指导支撑细胞染发细胞命运，并在产后内耳成熟，表观遗传障碍会阻止这些基因网络的重新激活。目的是开发克服这些表观遗传障碍的方法，并用 Corti器官内的再生潜力。在实验上，围产小鼠保留了直接支撑细胞转分解为A的潜在能力类似毛细胞的命运，但是这种能力在出生后的头几周迅速损失。这种与年龄有关的变化再生电位提供了一个窗口，可以通过该窗口研究从允许到一个的过渡在正常成熟的Corti中的这种再生形式的非允许状态。这项工作建议是阐明围产期支撑中转分化的表观遗传控制的机制细胞（AIM1）并确定与成熟相关的表观遗传/染色质结构的机制支撑内耳的细胞。（目标2）。我们假设这些变化是导致失败的原因再生。最后，研究正常和聋小鼠（AIM 3）。我们假设对表观遗传状态的操纵是一种重要方法未来的再生医学方法可以恢复失去的毛细胞。