Trophic interactions in developing and adult inner ear

发育中和成人内耳的营养相互作用

• 批准号: 6445095
• 负责人: Gabriel Corfas
• 金额: $ 34.58万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6445095
• 关键词: biological signal transduction; cochlea; developmental neurobiology; gene expression; genetically modified animals; growth factor receptors; histogenesis; immunocytochemistry; in situ hybridization; laboratory mouse; labyrinth; neuregulins; neurogenetics; polymerase chain reaction; tissue /cell culture; vestibular apparatus

DESCRIPTION (provided by applicant): Neuronal degeneration is a key determinant of impairment in many disorders of hearing and balance, and neuronal survival after hair cell loss is critical to the success of cochlear implants. Recent collaboration between our laboratories has suggested a role for the trophic factor neuregulin (NRG), and its receptors, the erbB family of tyrosine kinase receptors, in the normal development, proliferation and post-natal survival of hair cells and their sensory innervation. We developed a transgenic mouse in which normal NRG-erbB signaling is disrupted in the ear. Phenotypic analysis revealed a hearing disorder associated with post-natal, primary degeneration of cochlear nerve fibers (without hair cell loss) and a balance disorder associated with a reduction in the size of the vestibular sensory epithelium and the vestibular ganglion. Based on this transgenic mouse, the first cochlear model of primary post-natal neuronal degeneration, we hypothesize that NRG released by sensory neurons binds to erbB receptors on supporting cells in both cochlear and vestibular epithelia. In the cochlea, we hypothesize that NRG-erbB signaling causes support cells to release neurotrophins, e.g. NT-3, which, in turn, promote neuronal survival. In vestibular organs, we hypothesize that NRG-erbB signaling causes support-cell and hair-cell proliferation which indirectly promotes neuronal survival. This proposal combines expertise in cellular and molecular studies of neuronal development and survival with expertise in morpho-physiological characterization of ear disorders to test and refine these hypotheses concerning the role of NRG-erbB signaling in inner ear development and maintenance. Specific aims use a combination of light and electron-microscopic morphometry, immunohistochemistry, in situ hybridization, quantitative RT-PCR and tissue culture to analyze the spatial and temporal expression patterns of key molecules in this signaling pathway (Aim 1); investigate, both in vivo and in vitro, the role of NRG-erbB signaling in the cochlea (Aim 2) and vestibular organs (Aim 3), and analyze the roles of NRG in the interactions between supporting cells and sensory neurons, using co-cultures. Completion of these aims will clarify important cellular and molecular mechanisms underlying the normal development and survival of hair cells and neurons in the inner ear. Results may help in devising treatments to prevent or retard neuronal degeneration and/or induce hair cell proliferation in sensorineural ear disorders.

描述（由申请人提供）：神经元变性是一个关键决定因素 许多听力和平衡障碍的损害，以及神经元的存活 毛细胞丧失后对耳蜗植入的成功至关重要。最近 我们实验室之间的合作表明， 神经调节因子（NRG）及其受体，酪氨酸激酶erbB家族 受体，在正常发育，增殖和出生后的生存 毛细胞及其感觉神经支配。我们开发了一种转基因小鼠， 正常的NRG-erbB信号在耳中被破坏。表型分析 揭示了与出生后，原发性退化相关的听力障碍， 耳蜗神经纤维（无毛细胞损失）和平衡障碍 与前庭感觉上皮的大小减少有关 和前庭神经节 基于此转基因小鼠，第一个耳蜗模型的初级出生后， 神经元变性，我们假设感觉神经元释放的NRG 与耳蜗和前庭支持细胞上的erbB受体结合 上皮细胞在耳蜗中，我们假设NRG-erbB信号导致 支持细胞释放神经营养因子，例如NT-3，其反过来促进 神经元存活在前庭器官中，我们假设NRG-erbB信号传导 导致支持细胞和毛细胞增殖， 神经元存活 该提案结合了神经元细胞和分子研究的专业知识， 在形态生理学方面的专业知识， 表征耳部疾病，以测试和完善这些假设 关于NRG-erbB信号在内耳发育中的作用， 上维护特定的目标使用光和电子显微镜的组合 形态计量学，免疫组织化学，原位杂交，定量RT-PCR 和组织培养，分析空间和时间表达模式， 该信号通路中的关键分子（目的1）;研究，无论是在体内还是 在体外，NRG-erbB信号传导在耳蜗（目的2）和前庭中的作用 器官（目标3），并分析NRG在器官之间相互作用中的作用 支持细胞和感觉神经元，使用共培养物。 这些目标的完成将阐明重要的细胞和分子 毛细胞正常发育和存活的机制， 内耳的神经元结果可能有助于设计治疗方法，以预防或 延缓神经元变性和/或诱导毛细胞增殖 感觉神经性耳部疾病