Epigenetic mechanisms triggering differentiation and plasticity in the developing organ of Corti

表观遗传机制触发发育中的柯蒂器官的分化和可塑性

• 批准号: 10170311
• 负责人: Talon Anthony Trecek
• 金额: $ 4.34万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170311
• 关键词: ATAC-seq; Acetylation; Acetyltransferase; Adopted; Affect; Age; Biological Assay; Cell Death; Cell Differentiation process; Cells; ChIP-seq; Chemicals; Cochlea; Data; Development; Electronics; Embryo; Epigenetic Process; Excision; Failure; Future; Gene Silencing; Genes; Genetic Models; Genetic Transcription; Hair Cells; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Immunofluorescence Immunologic; In Situ Hybridization; Individual; Knowledge; Labyrinth; Link; Lysine; Maintenance; Mitotic; Molecular; Natural regeneration; Organ of Corti; Outcome; Pathway interactions; Perinatal; Pharmaceutical Preparations; Process; Regenerative Medicine; Regenerative research; Regulator Genes; Role; Running; Sensory; Sensory Hair; Severities; Specific qualifier value; Stains; Supporting Cell; Supporting Cell of Organ of Corti; Techniques; Testing; Therapeutic; Time; Transferase; Travel; assault; base; cell type; conditional knockout; deafness; demethylation; drug discovery; epigenetic marker; epigenetic profiling; experimental study; genome-wide; hair cell regeneration; hearing impairment; hearing restoration; histone acetyltransferase; in vivo; inhibitor/antagonist; mouse genetics; mouse model; notch protein; ototoxicity; perinatal period; progenitor; programs; stem cells; transcription factor; transcriptome sequencing; transdifferentiation

Project Summary/Abstract Hearing loss affects most individuals, with increasing severity as we age. The primary cause is the loss of sensory hair cells within the organ of Corti. Hair cells do not regenerate and so what you are born with must last a lifetime, an increasingly difficult task given the constant assault from electronics, machinery, and ototoxic drugs. Efforts to induce regeneration of hair cells, while highly promising, have run into numerous problems. In early development, supporting cells of the organ of Corti can be chemically induced to transdifferentiate to hair cells, thus achieving limited regeneration. As supporting cells mature, they lose their plasticity and are no longer able to transdifferentiate. To make regeneration of hair cells and restoration of hearing feasible, we must overcome this barrier. The loss of plasticity during development is a common dilemma in a variety of cell types, and has become increasingly attributed to epigenetic mechanisms. In this proposal, I investigate the role of the epigenetic modifiers Prc2 and Kdm6b in the plasticity of early support cells of the cochlea and their subsequent loss of plasticity. To do so I conduct inhibitor studies, ChIP-seq experiments, and use mouse genetic models. My findings will help us understand the mechanisms blocking regeneration of hair cells, and expand our general understanding of how cell types are established. Identifying the epigenetic regulators, Prc2 and Kdm6b, responsible for supporting cell plasticity would move the field past this barrier to regeneration, and provide the targets for future drug discovery.

项目总结/摘要 听力损失影响大多数人，随着年龄的增长，严重程度越来越高。主要原因是损失 感觉毛细胞的神经元毛细胞不能再生，所以你出生时就必须 持续一生，由于电子，机械和耳毒性的不断攻击， 毒品诱导毛细胞再生的努力虽然非常有希望，但遇到了许多问题。在 在发育早期，可通过化学诱导Corti器官的支持细胞转分化为毛发 细胞，从而实现有限的再生。随着支持细胞的成熟，它们失去了可塑性， 更长的时间可以进行转分化。为了使毛细胞再生和听力恢复可行，我们 必须克服这个障碍。发育过程中可塑性丧失是多种细胞共同面临的困境 类型，并已越来越多地归因于表观遗传机制。在这个建议中，我调查了 表观遗传修饰因子Prc 2和Kdm 6 b在耳蜗早期支持细胞可塑性中的作用 随后失去可塑性。为此，我进行了抑制剂研究，ChIP-seq实验，并使用小鼠 基因模型我的发现将帮助我们了解阻碍毛细胞再生的机制， 扩展我们对细胞类型如何建立的一般理解。鉴定表观遗传调节因子Prc 2 和Kdm 6 b，负责支持细胞的可塑性，将移动领域过去这一障碍，以再生， 为未来的药物发现提供了靶点。