Gene-Expression Patterns During Hair-Cell Regeneration

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。具体的挑战题目是11-DC-101，毛细胞再生和维护。耳聋和轻度听力障碍对现代社会有着巨大的影响。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。在美国，听力疾病每年造成的损失超过800亿美元，除此之外，听力疾病还会延迟婴儿的语言习得，使老年人孤立，并使所有年龄段的患者感到沮丧。一个有希望的途径，以减轻耳聋是恢复正常听力的再生毛细胞在人耳蜗。我们希望确定特定的基因，其激活基础上的毛细胞的更新，其受体通常翻转物种。特别是，我们希望研究斑马鱼幼虫的侧线器官，其中毛细胞再生已被详细描述。我们将首先确定哪些分子信号是由毛细胞死亡激活的，这是再生的刺激。我们下一步计划确定当静止干细胞和扩增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功能性毛细胞时哪些途径被上调。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听力。识别干细胞和毛细胞祖细胞基因表达的变化将为研究毛细胞再生开始时激活的信号通路提供线索。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干细胞的活性，因此这些途径构成了人类耳蜗和前庭器官毛细胞再生治疗方法的逻辑靶点。毛细胞再生过程中的基因表达模式

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.