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

基本信息

批准号：
9535977
负责人：
Michael Anne NMI Gratton
金额：
$ 41.57万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
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/9535977
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

项目摘要

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+ 通过各种 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+ 调节头发的电学和生化特性。我们实验室和其他实验室之前的研究在鉴定 HC 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+ 介导的功能的细胞机制仍不清楚。此外，Ca2+ 还通过仍然未知的机制激活一些外向通道电流，例如 Ca2+ 激活的 Cl- 通道。该提案的总体目标是部署创新。分子生物学、电生理学和成像技术，其中许多受到以前的 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领域。该提案推动了解决 HC 和 HC 的三个目标。 SGN Ca2+ 介导的生理学，每一个都具有基本和治疗意义。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。目的是：1) 明确解决这些功能。 2) 确定听力前到听力后 SGN 特征转变的 Ca2+ 介导机制，最后 3) 确定 SGN 中 Ca2+ 通道的不同亚型。确定听力出现前 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后，突触前和突触后的联合活动会增强内部 HC (IHC) 型 1-SGN 突触。总体而言，该提案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、成像和生化工具来回答 Ca2+ 介导的电和生化变化的基本未知。 HC 和 SGN 生理学。事实上，我们的研究结果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发现，即发展中的 SGN 是自发活跃的，这可能会改变 SGN 的生长。模式以及突触的形成可能会对新型人工耳蜗的设计产生可测量的影响，并提高精度和准确度。