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.

项目摘要 数以百万计的美国人遭受无情的慢性疼痛状况， 治疗，而那些转向阿片类药物的人可能会产生毁灭性的依赖性， 危及生命有必要对更有效的，非成瘾性的镇痛剂，有限的副作用， 方面的影响.电压门控钙（CaV）通道是改善疼痛疗法的潜在靶点。Cav 通道在改变感觉神经元的敏感性和传递有害物质的信息方面至关重要。 刺激。感觉神经元对刺激（如热和触摸）的敏感性变化可能导致 短暂形式的超敏反应，如果刺激持续时间长或特别强烈，则更长 过敏，这可能导致慢性疼痛。脊髓中的CaV通道对于 诱导和维持超敏反应，但Lipscombe实验室最近表明，外周 皮肤中的热感受神经元中的CaV2.2通道对于这一过程也是至关重要的。这项建议会 扩展这一发现，以研究外周CaV通道的功能贡献， 大鼠Trpv 1-伤害性感受器和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，光遗传学和自动化，实时行为跟踪与高速摄像将 结合以评估由Trpv 1-伤害感受器的直接激活诱导的行为反应 （热感应）或Aδ LTMR（机械感应）。诱发行为的变化将在以下情况下进行评估 任何一种神经元群体的敏化以及选择性抑制外周CaV的潜力 通道来衰减这些输出。目的2研究神经细胞内钙动力学 皮肤中与超敏反应发展相关的末梢。光遗传学集成，双光子 体内钙成像和药理学将揭示CaV2.2和CaV3.2的单独贡献 Trpv 1-伤害感受器和Aδ LTMR中触发超敏反应的钙离子通道。这项工作 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， 可以确定新的作用位点，用于开发更有效的疼痛治疗剂，从而减少 中枢神经系统的副作用。拟议的研究建立在 申请人的经验，并提供了一个机会，发展独特的专业知识，在遗传，行为，2- 光子成像和计算技术。与Fleischmann和摩尔实验室合作， 光子钙成像为申请人提供了团队科学和跨学科整合的重要经验。 不同层次的调查。该奖学金还将支持申请人的专业发展 严格的科学方法和有效的科学交流。脑科学环境 布朗大学是特殊的培训，它提供了许多途径的支持，培训， 为申请人作为独立学术科学家的职业生涯做准备的资源。