CRCNS: Molecular and Computational Dissection of Cold Nociception

CRCNS：冷伤害感受的分子和计算剖析

• 批准号: 9977816
• 负责人: GENNADY S CYMBALYUK
• 金额: $ 33.98万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977816
• 关键词: Acute Pain; Address; Afferent Neurons; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Biological Models; Biophysics; Categories; Code; Complex; Computer Models; Coupled; Detection; Dissection; Drosophila genus; Electrophysiology (science); Estrogen receptor positive; Fibromyalgia; Functional Imaging; Goals; Health; Homeostasis; Hypersensitivity; Image; Instruction; Investigation; Ion Channel; Ions; Knowledge; Lead; Light; Link; Mechanics; Mediating; Modality; Molecular; Molecular Computations; Multiple Sclerosis; Neurologic; Neurons; Nociception; Nociceptive Stimulus; Organism; Outcomes Research; Output; Pain; Pain Measurement; Pattern; Perception; Physiological; Play; Principal Investigator; Process; Property; Proteins; Role; Route; Sensory; Signal Transduction; Stimulus; Stroke; System; TRP channel; Temperature; Temperature Sense; Testing; Tissues; base; behavioral response; cellular imaging; chemotherapy induced neuropathy; chronic pain; experience; in vivo; insight; models and simulation; multimodality; nervous system disorder; neural patterning; neurogenetics; neurogenomics; pain sensation; painful neuropathy; receptor; relating to nervous system; response; sensory stimulus; somatosensory; spatiotemporal; stroke patient; tool

The long-term goal of this proposal is to understand the molecular and physiological bases of cold nociception. Thermosensory nociception is a specialized form of somatosensation essential to the survival of all metazoans. Thermosensory nociception alerts the organism to potential environmental dangers coupled with pain sensation thereby serving as a protective mechanism for driving adaptive behavioral responses to safeguard against incipient damage. Despite this importance, the fundamental molecular and biophysical bases of cold nociception remain poorly understood. Molecularly, transient receptor potential channels (i.e. thermoTRPs) play critical roles in thermosensation, however, relatively less is known regarding how thermoTRPs mechanistically function in regulating noxious cold detection. Neurologically, acute and chronic pain may manifest as altered thermosensory nociception whereby innocuous thermal stimuli erroneously engage nociceptive circuitry leading to neuropathic pain. Cold hypersensitivity is associated with multiple sclerosis, fibromyalgia, stroke, and chemotherapy-induced neuropathy resulting in neuropathic pain, however the mechanisms underlying cold sensitization are largely unknown. Here, we will investigate a fundamental problem of how multimodal sensory neurons discriminately detect noxious cold stimuli to elicit nocict9ptive behavior using Drosophila as a model system in combination with bi- directionally linked neurogenetic, neurogenomic, cellular imaging, electrophysiological, behavioral, computational modeling, and bifurcation analyses. We aim to uncover molecular and biophysical bases for cold-evoked nociceptive stimulus coding, including the functional properties of thermoTRPs and Ca2· signaling dynamics in this process. The project aims and outcomes of this research will significantly advance our knowledge of cold nociception by addressing three open questions: (1) What are the molecular and biophysical bases of cold nociceptive stimulus coding? (2) How do multimodal nociceptive neurons discriminately detect noxious stimuli (e.g. cold) to drive nocifensive behavior? (3) How do thermoTRPs and Ca2· signaling mechanisms mechanistically function in regulating noxious cold detection? More generally, the bi-directional integration of experimental and computational approaches in a closed- loop investigational strategy is well-suited to transform our understanding of cold nociception by elucidating potentially generalizable mechanisms of cold thermosensory coding, including roles of TRP channels and. Ca2· homeostasis in sensory-evoked neural activity. RELEVANCE (See instructions): The perception of noxious stimuli is often coupled to pain sensation as a protective mechanism, however altered temperature sensation may lead to neuropathic pain (e.g. in multiple sclerosis, fibromyalgia, and stroke) where patients experience pain due to cold hypersensitivity. By uncovering basic mechanisms of noxious cold perception, we develop important insights on neural integration of painful stimuli providing potential routes for understanding and treating neurological disease when this process is disrupted.

该提议的长期目标是了解冷的分子和物理基础 伤害感受。热感觉伤害感受是一种适合生存必不可少的体感应形式 在所有后生人中。热感觉伤害吸引力提醒有机体对潜在的环境危险 再加上疼痛感，从而作为驱动适应性行为的保护机制 对保护初期损害的响应。尽管如此，但基本分子和 冷鼻孔的生物物理基础仍然了解不足。分子的瞬时受体电势 但是，通道（即ThermotRP）在热效中起关键作用，但是，相对较少的 关于ThermoTRP如何在控制有害冷检测中机械起作用。神经学上， 急性和慢性疼痛可能表现为改变的热感性伤害感受，从而无效 刺激错误地接合伤害性电路，导致神经性疼痛。冷高敏性是 与多发性硬化症，纤维肌痛，中风和化学疗法诱导的神经病相关，导致 神经性疼痛，然而，冷敏感的基本机制在很大程度上尚不清楚。在这里，我们 将研究一个基本问题，即多模式感觉神经元如何歧视有害 冷刺激以使用果蝇作为模型系统与Bi-的结合引起nocict9的行为 定向连接的神经遗传学，神经基础，细胞成像，电生理，行为，行为， 计算建模和分叉分析。我们旨在发现分子和生物物理碱 冷诱发的伤害性刺激编码，包括ThermoTRP和CA2·的功能特性 在此过程中的信号动力学。该项目的目标和结果将大大显着 通过解决三个开放问题：（1）什么是什么？ 冷伤害性刺激编码的分子和生物物理碱基？ （2）多模式伤害感受 神经元区分检测有害刺激（例如冷）以驱动单位行为？ （3）如何 ThermotRP和CA2·信号传导机制在确定有害冷检测方面机械起作用？ 更一般地，在封闭式中实验和计算方法的双向整合 循环研究策略非常适合通过阐明我们对寒冷伤害感受的理解 冷热感应编码的潜在可推广机制，包括TRP通道和。 Ca2·感官诱发的神经活动中的稳态。 相关性（请参阅说明）： 有害刺激的感知通常与疼痛感耦合为一种保护机制，但是 温度感觉改变可能导致神经性疼痛（例如，在多发性硬化症中，纤维肌痛和 中风）患者由于低温而导致疼痛。通过发现的基本机制 有害的感冒感，我们就痛苦的神经元整合提供了重要的见解 当此过程中断时，理解和治疗神经系统疾病的潜在途径。