Calcium-dependent functions in Hair Cells and Spiral Ganglion Neurons

 描述（由申请人提供）：Ca 2+通过多种Ca 2+通道（Cav）亚型以及非特异性阳离子通道（如机械门控通道）进入细胞。进入后，Ca 2+调节毛细胞（HC）和螺旋神经节神经元（SGN）的电和生物化学性质。我们实验室和其他实验室的先前研究在HCs和SGN中鉴定多个Ca 2+介导的信号传导方面取得了重要的新发现。然而，这种Ca 2+介导的功能的细胞机制仍不清楚。此外，Ca 2+激活几种外向通道电流，例如Ca 2+激活的Cl-通道，其机制仍然未知。该提案的总体目标是部署创新的分子生物学，电生理学和成像技术，许多灵感来自以前的钙离子通道研究，用于发现SGNs中Ca 2+介导的生理学的基础和新的可访问领域。这一建议推动了三个目标，解决HC和SGN Ca 2+介导的生理学，每一个都具有基本和治疗意义。 总体假设是Ca 2+流入SGN调节不同的功能，从短期膜兴奋性到长期发育过程。目的：1）明确SGN中不同类型Ca ~（2+）通道的功能。2)以确定Ca 2+介导的机制，潜在的转化的前到后的SGN的特点和最后3）确定潜在的机制，重组混杂的神经支配的HC SGN在听力发作之前。我们预测，结合突触前和突触后活动加强内部HC（IHC）型1-SGN突触后，最初的不分青红皂白的接触。 该项目将使用不同的小鼠模型及其相应的年龄匹配对照，以及生理，成像和生化工具进行。总的来说，这个建议将回答基本未知的钙离子介导的电和生化变化的HC和SGN生理。事实上，我们的发现很可能揭示病理性听觉现象的机制，并在这样做的过程中，促进我们努力设计新的治疗策略。发现发育中的SGN是自发活动的，这可能会改变SGN生长模式以及突触形成，这可能会对设计具有更高精度和准确性的新型人工耳蜗植入物产生可测量的影响。

 DESCRIPTION (provided by applicant): Ca2+ enters into cells through a variety of Ca2+ channel (Cav) subtypes, as well as non-specific cationic channels, such as mechanically-gated channels. Upon entry, Ca2+ regulates the electrical and biochemical properties of hair cells (HCs) and spiral ganglion neurons (SGNs). Previous studies from our laboratory and others have made important new discoveries on the identification of the multiple Ca2+-mediated signaling in HCs and SGNs. However, the cellular mechanism of this Ca2+-mediated functions remains unclear. Additionally Ca2+ activates several outward channel currents, such as Ca2+-activated Cl- channels through mechanisms that still remains unknown. The overall goal of this proposal is to deploy innovative molecular biological, electrophysiological, and imaging techniques, many inspired from previous Ca2+ channel studies, for the discovery of fundamental and newly accessible arenas of Ca2+-mediated physiology in SGNs. This proposal drives three aims that address the HC and SGN Ca2+-mediated physiology, each with fundamental and therapeutic implications. The overall hypothesis is Ca2+ inflow into SGNs regulates distinct functions, ranging from short-term membrane excitability to long-term developmental processes. The Aims are: 1) To unequivocally resolve the functions of distinct subtypes of Ca2+ channels in SGNs. 2) To determine Ca2+-mediated mechanisms underlying the transformation of the features of pre- to post-hearing SGNs and finally 3) To determine the mechanisms underlying the reorganization of promiscuous innervation of HCs by SGNs prior to hearing onset. We predict that combined pre- and post-synaptic activities strengthen inner HC (IHC)-type 1-SGN synapse following initial indiscriminate contacts. The project will be conducted using different mouse models and their corresponding age-matched controls, as well as physiological, imaging and biochemical tools. Overall, this proposal will answer fundamental unknowns of Ca2+-mediated electrical and biochemical changes in HC and SGN physiology. Indeed, our findings are likely to reveal the mechanisms of pathological auditory phenomena, and in doing so, facilitate our efforts to design new therapeutic strategies. The discovery that developing SGNs are spontaneously active, and that this may alter SGN growth pattern as well as synapse formation are likely to have measurable impact in the design of new cochlear implants with increased precision and accuracy.