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: 9914459
• 负责人: GENNADY S CYMBALYUK
• 金额: $ 33.8万
• 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/9914459
• 关键词: Acute Pain; Address; Afferent Neurons; Automobile Driving; Behavior; Behavioral; Behavioral Assay; Biological Models; Biophysics; Categories; Code; Complex; Computer Simulation; Coupled; Detection; Dissection; Drosophila genus; Electrophysiology (science); 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.

该提案的长期目标是了解寒冷的分子和生理基础 伤害感受是一种对生存至关重要的特殊形式的躯体感觉。 所有后生动物的热感觉伤害感受提醒生物体潜在的环境危险。 与疼痛感相结合，从而作为驱动适应性行为的保护机制 尽管这一点很重要，但基本的分子和机制仍然存在。 冷痛感受的生物物理基础仍然知之甚少，瞬时感受器的潜力。 通道（即ThermoTRP）在热感觉中发挥着关键作用，但人们知之甚少 关于thermoTRPs如何在神经学上调节有害寒冷检测中发挥作用。 急性和慢性疼痛可能表现为热感觉伤害性感受，从而产生无害的热 刺激错误地参与伤害性回路，导致神经性疼痛。 与多发性硬化症、纤维肌痛、中风和化疗引起的神经病变相关 神经性疼痛，然而冷敏化背后的机制很大程度上是未知的。 将研究多模式感觉神经元如何区分检测有害物质的基本问题 使用果蝇作为模型系统并结合双-冷刺激来引发伤害性行为 定向关联神经遗传学、神经基因组学、细胞成像、电生理学、行为学、 我们的目标是揭示分子和生物物理基础。 冷诱发的伤害性刺激编码，包括ThermoTRPs和Ca2·的功能特性 本研究的项目目标和成果将显着影响这一过程中的信号动态。 通过解决三个悬而未决的问题，我们对冷痛觉的了解不断加深：（1）什么是冷痛觉？ (2) 多模式伤害性感受如何 神经元有区别地检测有害刺激（例如寒冷）以驱动伤害行为？（3）如何做？ ThermoTRP 和 Ca2· 信号机制在调节有害寒冷检测中发挥机制作用？ 更一般地说，实验和计算方法在封闭的环境中的双向集成 循环研究策略非常适合通过阐明冷伤害感受来改变我们对冷伤害感受的理解 冷热感觉编码的潜在可推广机制，包括 TRP 通道的作用和。 感觉诱发神经活动中的 Ca2· 稳态。 相关性（参见说明）： 然而，对有害刺激的感知通常与疼痛感相结合，作为一种保护机制 温度感觉的改变可能导致神经性疼痛（例如多发性硬化症、纤维肌痛和 通过揭示中风的基本机制，患者会因冷过敏而感到疼痛。 有害的冷知觉，我们对疼痛刺激的神经整合产生了重要的见解，提供了 当这一过程被破坏时，了解和治疗神经系统疾病的潜在途径。