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.

项目总结 数以百万计的美国人遭受着无情的慢性疼痛状况的折磨，这些疾病抵抗着现有的 治疗，而那些转向阿片类药物治疗的人可能会产生毁灭性的依赖 有生命危险。迫切需要更有效、不会上瘾、副作用有限的止痛药 效果。电压门控钙通道(Cav)是改善疼痛治疗的潜在靶点。洞穴 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是至关重要的。 刺激物。感觉神经元对刺激敏感性的变化--如热和触摸--可能导致 短暂形式的过敏症，如果刺激时间延长或特别强烈，则时间更长 过敏症，会导致慢性疼痛。脊髓中的CAV通道对 诱导和维持超敏反应，但Lipscombe实验室最近表明，外周血细胞 皮肤热敏神经元中的Cav2.2通道也是这一过程的关键。这项提议将 扩展这一发现以研究外周CAV通道对 TRPV1伤害性感受器和δ低阈值机械感受器(AδLTMR)神经末梢的超敏反应 皮肤。在目标1中，光遗传学和带有高速摄像的自动、实时行为跟踪将 联合评估直接激活TRPV1-伤害性感受器引起的行为反应 (热敏)或AδLTM(机械传感)。诱发行为的变化将在以下方面进行评估 任一神经元群体的敏化以及选择性抑制外周空洞的可能性 衰减这些输出的通道。AIM 2将研究神经细胞内钙动力学 皮肤的末梢与超敏反应的发展有关。光遗传学、双光子集成 活体钙成像和药理学将揭示Cav2.2和CaV3.2的个体贡献 在触发超敏反应的TRPV1伤害性感受器和AδLTMR中钙事件的通道。这部作品 将提供关于外周CAV通道在诱导超敏反应和 可能会确定新的作用部位，以开发更有效的疼痛疗法，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，并提供了一个机会，以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Moore实验室合作2- 光子钙成像使申请者具备团队科学和跨领域集成的基本经验 不同级别的调查。这项奖学金还将支持申请者的专业发展 严谨的科学方法和有效的科学交流。的脑科学环境 布朗大学在培训方面是独一无二的，它提供了许多支持、培训和 为申请者成为独立的学术科学家做好准备的资源。