Enhancing Atoh1 function in hair cell regeneration

增强 Atoh1 在毛细胞再生中的功能

• 批准号: 9052500
• 负责人: Andrew K Groves
• 金额: $ 64.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052500
• 关键词: Adenoviruses; Adult; Age; Animals; Binding; Biological Assay; Birds; Cause of Death; Cell Aging; Cell Survival; Cells; ChIP-seq; Cochlea; Collaborations; Complex; Consensus; DNA Methylation; Data; Drosophila genus; Ectopic Expression; Embryo; Engineering; Epigenetic Process; Fishes; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Goals; Grant; Hair Cells; Health; Hearing; Hematopoietic System; Histones; Homologous Gene; Human; Injury; Knock-in Mouse; Mammals; Mediating; Medicine; Michigan; Modification; Mus; Mutant Strains Mice; Natural regeneration; Neonatal; Organ of Corti; Production; Rana; Reagent; Recruitment Activity; Reporter; Sensorineural Hearing Loss; Sensory Hair; Small Ubiquitin-Related Modifier Proteins; Supporting Cell; System; Testing; Time; Tissues; Universities; Vertebrates; Work; Zinc Fingers; age related; base; bisulfite sequencing; cell age; college; epigenetic regulation; hair cell regeneration; hearing impairment; histone methylation; histone modification; in vivo; mutant; regenerative; transcription factor; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): Sensorineural hearing loss is caused by the death of hair cells in the organ of Corti, and once lost, cochlear hair cells in humans and other mammals do not regenerate. In contrast, non-mammalian vertebrates can functionally recover from deafening injury by mobilizing supporting cells to divide and differentiate to replace lost hair cells. Over the last 10 years, the consensus from many studies is that supporting cells in the embryonic and neonatal organ of Corti retain a limited capacity to divide and differentiate into hair cells under certain conditions, but that this ability declines precipitously prior to the onse of hearing. One facet of such an age-dependent decline in regenerative potential is the function of the transcription factor Atoh1. Ectopic expression of Atoh1 in embryonic or neonatal cochlear tissue can transform supporting cells or adjacent non-sensory into hair cells - but this ability appears to be severely diminished after the onset of hearing in mice. The goal of this proposal is to understand why the ability of Atoh1 to drive cochlear hair cell regeneration declines with age. Although there are many possible mechanisms for this age-dependent decline, we will test just two in the current proposal. First, we hypothesize that at least some of the transcriptional target of Atoh1 become epigenetically modified in supporting cells with age, rendering them unavailable for transcription. Our second hypothesis, which is not mutually exclusive with the first, is that Atoh1 requires transcriptional co-factors that are not present in the mature cochlea Studies from Drosophila and our preliminary data have identified the zinc finger transcription factor Gfi1 as a good candidate to potentiate the activity of Atoh1 during hair cell formation.

 描述（由适用提供）：感官听力损失是由Corti器官中毛细胞死亡引起的，一旦丢失，人类和其他哺乳动物的耳蜗细胞就不会再生。相反，非哺乳动物脊椎动物可以通过动员支持细胞分裂和区分以替代丢失的毛细胞来从功能上恢复聋哑损伤。在过去的十年中，许多研究的共识是，在某些条件下，Corti的胚胎和新生儿器官中的支撑细胞保留了有限的能力和分化为毛细胞的能力，但是这种能力的下降精确是在听证会之前。这种年龄依赖性下降的再生潜力下降的一个方面是转录因子ATOH1的功能。 ATOH1在胚胎或新生儿耳蜗组织中的异位表达可以将支持细胞或邻近的非敏感性转化为毛细胞 - 但是在小鼠听力发作后，这种能力似乎严重降低。该提案的目的是了解为什么ATOH1推动人工耳蜗再生的能力随着年龄的增长而下降。尽管这种依赖年龄的下降有许多可能的机制，但我们将在当前提案中仅测试两个。首先，我们假设至少某些ATOH1的转录靶标在随着年龄的增长的支撑细胞方面进行了表观修饰，从而使它们无法进行转录。我们的第二个假设与第一个并非互斥的假设是ATOH1需要果蝇成熟的耳蜗研究中不存在的转录co因子，而我们的初步数据已将锌指转录因子GFI1鉴定为良好的候选ATOH1的潜在植物细胞形成的活性。