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: 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
• 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

 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（由适用提供）：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+调节毛细胞（HCS）和螺旋神经神经元（SGN）的电和生化特性。我们实验室和其他人的先前研究对HCS和SGN中多个CA2+介导的信号传导的识别提出了重要的新发现。但是，该CA2+介导的功能的细胞机制尚不清楚。此外，Ca2+通过仍然未知的机制激活了几种外向通道电流，例如Ca2+激活的Cl-通道。该提案的总体目标是部署创新的分子生物学，电生理和成像技术，这是许多受到先前CA2+通道研究的启发，以发现SGN中Ca2+介导的生理学的基本和新近可访问的领域。该提案推动了针对HC和SGN CA2+介导的生理学的三个目标，每个生理学都具有根本和治疗的影响。总体假设是Ca2+流入SGNS可以调节不同功能，从短期膜到令人兴奋的长期发育过程。目的是：1）明确解决SGN中Ca2+通道不同亚型的功能。 2）确定在听证后SGN的特征转化为基础的Ca2+介导的机制，以确定在听力发作之前通过SGN重组HCS的机制。我们预测，在初始不加选择的接触后，突触前和突触后活性增强了内HC（IHC）型1-SGN突触。该项目将使用不同的鼠标模型及其相应的年龄匹配的控件以及物理，成像和生化工具进行。总体而言，该建议将回答HC和SGN生理学中Ca2+介导的电和生化变化的基本未知数。确实，我们的发现很可能揭示了病理听觉现象的机制，并在此过程中促进了我们为设计新理论策略的努力。发现开发SGN具有赞助的发现，并且这可能会改变SGN的生长模式以及突触的形成可能会对新的耳蜗粉丝的设计产生可衡量的影响，其精度和准确性提高。