Gene-Expression Patterns During Hair-Cell Regeneration

毛细胞再生过程中的基因表达模式

• 批准号: 7817295
• 负责人: ALBERT JAMES HUDSPETH
• 金额: $ 22.35万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817295
• 关键词: Address; Affect; Age; Aminoglycoside Antibiotics; Area; Biological Assay; Biological Models; Cell Death; Cell Separation; Cells; Cochlea; Confocal Microscopy; Data; Development; Elderly; Enhancers; Equilibrium; Event; Feedback; Fluorescence-Activated Cell Sorting; Gene Chips; Gene Expression; Genes; Hair Cells; Hearing; Hearing problem; Human; Individual; Infant; Label; Labyrinth; Maintenance; Messenger RNA; Mitosis; Molecular; Natural regeneration; Operative Surgical Procedures; Organ; Pathway interactions; Pattern; Peripheral; Population; Preparation; Production; Regenerative Medicine; Side; Signal Pathway; Signal Transduction; Societies; Speech; Stem cells; Stimulus; Structure; Supporting Cell; Time; United States; Vertebrates; Vestibule; Zebrafish; base; cell type; cost; deafness; depressed; hair cell regeneration; hearing impairment; killings; lateral line; neuromast; progenitor; public health relevance; receptor; response; restoration; stem cell division; stem cell population; therapeutic target

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area 11, entitled Regenerative Medicine. The specific Challenge Topic is 11-DC-101, Hair Cell Regeneration and Maintenance. Deafness and lesser degrees of hearing impairment have an enormous impact on modern societies. Throughout the industrialized world, about one-tenth of the population suffers from functionally significant hearing and balance problems. The societal impact of hearing loss is immense. In addition to its annual cost in the United States of more than $80 billion, hearing disease delays the acquisition of speech in infants, isolates the elderly, and depresses affected individuals of all ages. A promising avenue to the alleviation of deafness is the restoration of normal hearing by regeneration of hair cells in the human cochlea. We wish to determine the particular genes whose activation underlies the renewal of hair cells in species whose receptors normally turn over. In particular, we hope to investigate the lateral-line organ of the larval zebrafish, a preparation in which hair-cell regeneration has been described in detail. We shall begin by ascertaining which molecular signals are activated by hair-cell death, the stimulus for regeneration. We next plan to determine the particular signaling pathways that are activated when quiescent stem cells and amplifying progenitors transition to their mitotically active states. Finally, we intend to understand what pathways are upregulated as immature cells differentiate into functional hair cells. The structure, development, and operation of hair cells are conserved throughout the vertebrates. We accordingly anticipate that a detailed understanding of the molecular events underlying hair-cell regeneration in a model system will be useful in restoring human hearing. Identifying the changes in gene expression by stem cells and hair-cell progenitors will provide clues about the signaling pathways that are activated at the outset of hair-cell regeneration. Because pharmacological manipulation of the relevant molecular signals may restore the activity of stem cells in the mammalian inner ear, these pathways constitute logical targets for therapeutic approaches to the regeneration of hair cells in the human cochlea and vestibular apparatus. Gene-expression patterns during hair-cell regeneration PUBLIC HEALTH RELEVANCE: Deafness and lesser degrees of hearing impairment have an enormous impact on modern societies: about one-tenth of our population suffers from functionally significant hearing and balance problems. A promising avenue to the alleviation of deafness is the restoration of normal hearing by regeneration of hair cells in the human cochlea. We wish to determine the signaling pathways that underlie the renewal of hair cells, for these pathways constitute logical targets for therapeutic approaches to the regeneration of hair cells in the human cochlea and vestibular apparatus.

描述(由申请人提供)：本申请涉及广泛的挑战领域11，题为再生医学。具体的挑战主题是11-DC-101，毛细胞再生和维护。耳聋和程度较轻的听力障碍对现代社会有巨大的影响。在整个工业化世界，大约十分之一的人口患有严重的听力和平衡问题。听力损失的社会影响是巨大的。听力疾病除了在美国每年造成800多亿美元的损失外，还会延迟婴儿获得语言的时间，孤立老年人，并使所有年龄段的受影响个人抑郁。减轻耳聋的一个有希望的途径是通过再生人类耳蜗毛细胞来恢复正常的听力。我们希望确定在受体正常翻转的物种中，哪些基因的激活是毛细胞更新的基础。特别是，我们希望研究斑马鱼幼体的侧线器官，这是一种已详细描述毛细胞再生的制备方法。我们将首先确定毛细胞死亡激活了哪些分子信号，毛细胞死亡是再生的刺激因素。我们下一步计划确定当静止的干细胞和扩增的祖细胞转变为有丝分裂活跃状态时激活的特定信号通路。最后，我们打算了解在未成熟细胞分化为有功能的毛细胞的过程中，哪些途径被上调。毛细胞的结构、发育和运作在整个脊椎动物中都是保守的。因此，我们预计，在模型系统中详细了解毛细胞再生的分子事件将有助于恢复人类的听力。识别干细胞和毛细胞前体细胞基因表达的变化将提供有关毛细胞再生开始时激活的信号通路的线索。由于对相关分子信号的药理学操作可能会恢复哺乳动物内耳中干细胞的活动，这些途径构成了治疗方法的合理靶点，以促进人类耳蜗器和前庭装置中毛细胞的再生。毛细胞再生过程中的基因表达模式 公共卫生相关性：耳聋和程度较轻的听力障碍对现代社会有巨大影响：我国约十分之一的人口患有严重的听力和平衡问题。减轻耳聋的一个有希望的途径是通过再生人类耳蜗毛细胞来恢复正常的听力。我们希望确定毛细胞更新背后的信号通路，因为这些通路构成了治疗方法的合理靶点，以在人类耳蜗器和前庭装置中再生毛细胞。