Calcium Signaling in Peripheral Sensory Nerve Endings

周围感觉神经末梢的钙信号传导

• 批准号: 10606853
• 负责人: Remy Meir
• 金额: $ 4.77万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606853
• 关键词: Address; Afferent Neurons; American; Analgesics; Attenuated; Behavior; Behavior assessment; Behavioral; Brain; Calcium; Calcium Channel; Calcium Channel Blockers; Calcium Signaling; Capsaicin; Central Nervous System; Collaborations; Communication; Computational Technique; Data; Dependence; Development; Environment; Event; Fellowship; Genetic; Hypersensitivity; Image; Imaging Techniques; Individual; Inflammation; Injury; Investigation; Knowledge; Life; Machine Learning; Maintenance; Measures; Mechanics; Mechanoreceptors; Mediating; Methodology; Methods; Modality; Mus; Nerve Endings; Nervous System; Neuroimmune; Neuronal Plasticity; Neurons; Nociceptors; Output; Pain; Peripheral; Peripheral Nerves; Pharmacology; Play; Population; Process; Pythons; Receptor Activation; Research; Resistance; Resources; Role; Science; Scientist; Sensory; Sensory Nerve Endings; Sensory Receptors; Signal Pathway; Signal Transduction; Site; Skin; Speed; Spinal Cord; Stimulus; Synaptic plasticity; Therapeutic; Time; Touch sensation; Training; Universities; Viral Vector; Work; behavioral response; career; chronic pain; chronic painful condition; delivery vehicle; experience; experimental study; improved; in vivo; in vivo calcium imaging; in vivo imaging; insight; intercellular communication; interest; large datasets; mechanotransduction; mouse model; neurogenetics; neurotransmission; novel; optogenetics; pain behavior; pharmacologic; prescription opioid; sensory stimulus; side effect; skills; statistics; therapeutic target; tool; transmission process; two-photon; voltage

PROJECT SUMMARY Millions of Americans suffer from unrelenting chronic pain conditions that are resistant to existing treatments, and those who turn to opioid medication can develop dependencies that are devastating and life threatening. There is essential need for more effective, non-addictive analgesics with limited side effects. Voltage-gated calcium (CaV) channels are potential targets for improved pain therapeutics. CaV channels are critical in altering sensory neuron sensitivity and in transmitting information about noxious stimuli. Changes in sensitivity of sensory neurons to stimuli – such as heat and touch - can result in transient forms of hypersensitivity and, if the stimulus is prolonged or especially intense, more prolonged hypersensitivity, which can lead to chronic pain. CaV channels in the spinal cord are important for the induction and maintenance of hypersensitivity, but the Lipscombe lab has recently shown that peripheral CaV2.2 channels in heat sensing neurons in skin are also critical for this process. This proposal will expand this discovery to investigate the functional contribution of peripheral CaV channels to hypersensitivity in Trpv1-nociceptor and Aδ low threshold mechanoreceptor (Aδ LTMR) nerve endings in skin. In Aim 1, optogenetics and automated, real-time behavior tracking with high-speed videography will be combined to assess behavioral responses induced by direct activation of either Trpv1-nociceptor (heat-sensing) or Aδ LTMRs (mechano-sensing). Changes in evoked behavior will be assessed following sensitization of either neuron population as well as the potential for selective inhibition of peripheral CaV channels to attenuate these outputs. Aim 2 will investigate intracellular calcium dynamics in nerve endings in skin associated with the development of hypersensitivity. Integration of optogenetics, 2-photon in vivo calcium imaging, and pharmacology, will uncover the individual contribution of CaV2.2 and CaV3.2 channels to calcium events in Trpv1-nociceptor and Aδ LTMRs that trigger hypersensitivity. This work will provide unique data on the role of peripheral CaV channels in the induction of hypersensitivity and may identify novel sites of action for developing more effective pain therapeutics, thereby reducing unwanted side effects from actions in the central nervous system. The proposed research builds on the applicant’s experience and provides an opportunity to develop unique expertise in genetic, behavioral, 2- photon imaging and computation techniques. Collaborating with the Fleischmann and Moore labs for 2- photon calcium imaging gives the applicant essential experience in team science and integrating across different levels of investigation. This fellowship will also support the applicant’s professional development in rigorous scientific methods and effective scientific communication. The Brain Science environment at Brown University is exceptional for training, it provides numerous avenues for support, training, and resources to prepare the applicant for a career as an independent academic scientist.

项目概要 数以百万计的美国人患有持续不断的慢性疼痛，这些疼痛对现有的药物有抵抗力。 治疗，以及那些转向阿片类药物的人可能会产生毁灭性的依赖性 危及生命。迫切需要更有效、非成瘾且副作用有限的镇痛药 影响。电压门控钙（CaV）通道是改善疼痛治疗的潜在目标。冠状病毒 通道对于改变感觉神经元敏感性和传输有害信息至关重要 刺激。感觉神经元对刺激（例如热和触摸）敏感性的变化可能会导致 短暂形式的超敏反应，如果刺激时间较长或特别强烈，则时间会更长 过敏，可导致慢性疼痛。脊髓中的 CaV 通道对于 诱导和维持超敏反应，但利普斯科姆实验室最近表明，外周 皮肤热传感神经元中的 CaV2.2 通道对于这一过程也至关重要。该提案将 扩展这一发现以研究外周 CaV 通道的功能贡献 Trpv1 伤害感受器和 Aδ 低阈值机械感受器 (Aδ LTMR) 神经末梢超敏反应 皮肤。在目标 1 中，光遗传学和利用高速摄像的自动化实时行为跟踪将 结合起来评估由直接激活 Trpv1 伤害感受器引起的行为反应 （热传感）或 Aδ LTMR（机械传感）。将评估诱发行为的变化 任一神经元群的敏化以及选择性抑制外周 CaV 的潜力 衰减这些输出的通道。目标 2 将研究神经细胞内钙动态 皮肤末端与超敏反应的发展有关。光遗传学整合，2-光子 体内钙成像和药理学将揭示 CaV2.2 和 CaV3.2 的个体贡献 Trpv1 伤害感受器和 Aδ LTMR 中触发超敏反应的钙事件的通道。这部作品 将提供关于外周 CaV 通道在诱导超敏反应中的作用的独特数据 可能会确定新的作用位点以开发更有效的疼痛治疗方法，从而减少 中枢神经系统活动产生的不良副作用。拟议的研究建立在 申请人的经验，并提供机会发展遗传、行为、2- 光子成像和计算技术。与 Fleischmann 和 Moore 实验室合作 2- 光子钙成像为申请人提供了团队科学和跨领域整合的重要经验 不同级别的调查。该奖学金还将支持申请人的专业发展 严谨的科学方法和有效的科学传播。脑科学环境 布朗大学在培训方面非常出色，它提供了多种支持、培训和培训的途径 为申请人作为独立学术科学家的职业生涯做好准备的资源。