Calcium-dependent functions in Hair Cells and Spiral Ganglion Neurons

毛细胞和螺旋神经节神经元的钙依赖性功能

• 批准号: 9750709
• 负责人: Michael Anne NMI Gratton
• 金额: $ 41.7万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750709
• 关键词: Action Potentials; Address; Adult; Age; Auditory; Biochemical; Biological; Birds; Brain; Brain-Derived Neurotrophic Factor; CLCA2 gene; Calcium; Cardiac; Cations; Cell physiology; Cells; Chemosensitization; Cochlear Implants; Data; Development; Developmental Process; Dihydropyridines; Electrophysiology (science); Ensure; Functional Imaging; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Glutamates; Goals; Grant; Growth; Hair Cells; Hearing; Histologic; Imaging Device; Imaging Techniques; In Vitro; Inner Hair Cells; Knowledge; Laboratories; Labyrinth; Link; Measurable; Mechanics; Mediating; Membrane; Metabotropic Glutamate Receptors; Molecular; NTF3 gene; Natural regeneration; Neurons; Neurotrophin 3; Pathologic; Pattern; Physiological; Physiology; Property; Protein Tyrosine Kinase; Publishing; Regulation; Research; Resolution; Role; SHH gene; Sensory; Signal Transduction; Source; Synapses; Techniques; Testing; Therapeutic; Trademark; Work; base; biochemical tools; bony labyrinth; cell type; design; experimental study; high resolution imaging; in vivo; innovation; insight; microscopic imaging; mouse model; nerve supply; novel; novel therapeutic intervention; postsynaptic; public health relevance; sound; spiral ganglion; synaptogenesis; voltage

 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.

 描述（由申请人提供）：Ca2+通过多种Ca2+通道（Cav）亚型以及非特异性阳离子通道（例如机械门控通道）进入细胞。进入后，Ca2+ 调节毛细胞 (HC) 和螺旋神经节神经元 (SGN) 的电学和生化特性。我们实验室和其他实验室之前的研究在鉴定 HC 和 SGN 中多种 Ca2+ 介导的信号传导方面取得了重要的新发现。然而，这种 Ca2+ 介导功能的细胞机制仍不清楚。此外，Ca2+ 还可以激活多个外向通道电流，例如 Ca2+ 激活的 Cl- 通道，其机制仍未知。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，其中许多技术受到以前的 Ca2+ 通道研究的启发，用于发现 SGN 中 Ca2+ 介导的生理学的基本和新的可用领域。该提案推动了三个目标，解决 HC 和 SGN Ca2+ 介导的生理学问题，每个目标都具有基础和治疗意义。 总体假设是 Ca2+ 流入 SGN 调节不同的功能，从短期膜兴奋性到长期发育过程。目标是： 1) 明确解析 SGN 中 Ca2+ 通道不同亚型的功能。 2) 确定 Ca2+ 介导的听力前 SGN 特征转变为听力后 SGN 特征的机制，最后 3) 确定听力开始前 SGN 重组 HC 混杂神经支配的机制。我们预测，在最初的不加区别的接触之后，突触前和突触后的组合活动会增强内部 HC (IHC) 型 1-SGN 突触。 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、成像和生化工具来进行。总体而言，该提案将解答 HC 和 SGN 生理学中 Ca2+ 介导的电和生化变化的基本未知问题。事实上，我们的发现很可能揭示病理性听觉现象的机制，并在此过程中促进我们设计新的治疗策略的努力。发育中的 SGN 是自发活跃的，这可能会改变 SGN 的生长模式以及突触形成，这一发现可能会对新型人工耳蜗植入物的设计产生重大影响，提高精度和准确度。