Trophic interactions in developing and adult inner ear

描述(申请人提供)：神经元变性是一个关键的决定因素 许多听力和平衡障碍以及神经元存活的损害 术后毛细胞丢失是人工耳蜗术成功与否的关键。近期 我们实验室之间的合作表明，营养 因子神经调节蛋白(NRG)及其受体--酪氨酸激酶的erbB家族 受体，在正常发育、增殖和出生后存活 毛细胞及其感觉神经。我们开发了一只转基因小鼠 哪个正常的NRG-erbB信号在耳朵中被破坏了。表型分析 发现了一种与产后听力障碍有关的原发变性 耳蜗神经纤维(无毛细胞丢失)和平衡障碍 与前庭感觉上皮大小缩小有关 还有前庭神经节。 在此转基因小鼠的基础上，首次建立了初级产后耳蜗鼠模型 神经元变性，我们假设NRG是由感觉神经元释放的 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，如NT-3，进而促进 神经元存活。在前庭器官中，我们假设NRG-erbB信号 导致支持细胞和毛细胞增殖，从而间接促进 神经元存活。 这一建议结合了神经细胞和分子研究方面的专业知识。 具有形态生理学专业知识的发育和生存 测试和完善这些假说的耳朵疾病的特征 关于NRG-erbB信号在内耳发育和 维修。特定目标使用光学和电子显微镜相结合的方法 形态计量学、免疫组织化学、原位杂交、定量RT-PCR 和组织培养，以分析其时空表达模式 该信号通路中的关键分子(目标1)；研究，在体内和 NRG-erbB信号在体外耳蜗区(Aim 2)和前庭的作用 器官(目标3)，并分析NRG在相互作用中的作用 支持细胞和感觉神经元，使用共培养。 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潜在机制和 内耳中的神经元。结果可能有助于设计治疗方法来预防或 延缓神经元变性和/或诱导毛细胞增殖 感觉神经性耳疾。

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.