Astrocyte Calcium Signaling in Neuropathic Pain

神经性疼痛中的星形胶质细胞钙信号传导

基本信息

批准号：
10540684
负责人：
Nicholas Alan Nelson
金额：
$ 4.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540684
关键词：
Acceleration Acute Acute Pain Affect American Analgesics Anatomy Anesthetics Animal Behavior Animal Model Arthritis Astrocytes Attention Basic Science Behavioral Behavioral Assay Brain Ca(2+)-Transporting ATPase Calcium Calcium Signaling Caring Cell membrane Central Nervous System Communication Data Dependence Development Disease Education Electrophysiology (science)Esthesia Gene Expression Genetic Genetic study Hypersensitivity Imaging Techniques Immune response Immunohistochemistry Inflammatory Response Institute of Medicine (U.S.)Intervention Knowledge Ligation Malignant Neoplasms Mammals Measurement Mechanics Mechanoreceptors Mediating Methods Modeling Molecular Morphology Mus Nerve Nervous System Physiology Neuroglia Neurons Nociception Nociceptors Organ Pain Pain Disorder Pain Research Pain management Pathogenesis Pathway interactions Pattern Peripheral Persistent pain Pharmacology Study Photons Physiological Play Posterior Horn Cells Pre-Clinical Model Process Productivity Publishing Reporting Reproducibility Research Resolution Role Sensory Signal Transduction Site Skin Spinal Spinal Cord Spinal cord injury Spinal cord posterior horn Techniques Tissues Translating Translations Vertebral column Work addiction cell type central sensitization chronic pain dorsal horn effective therapy experimental study histological studies imaging approach in vivo calcium imaging insight knock-down miniaturize nerve injury novel novel therapeutic intervention optogenetics pain behavior pain chronification pain signal painful neuropathy pharmacologic phase change pre-clinical prevent process improvement rational design receptor response sciatic nerve sensory integration sex side effect spatiotemporal temporal measurement transcriptome transcriptome sequencing two-photon

项目摘要

PROJECT SUMMARY Chronic pain is a hallmark of many disease conditions, including nerve and spinal cord injury. Current mainstays of pain management include analgesics and anesthetics, treatments that are used despite their uncertain efficacy and known side effects. Safer and more productive approaches for pain management are urgently needed, but knowledge gaps in basic research have hampered the development and translation of novel treatments. To accelerate this process an improved understanding of the cellular and molecular basis of pain signaling is required. The spinal cord is a crucial signaling hub involved in communicating pain-related signals between peripheral organs and the brain. As the first site of sensory integration within the central nervous system (CNS), it plays essential roles in central sensitization. Much attention has focused on the neuronal cell types and circuits that contribute to this process. However, considerably less is known about the contributions of non-neuronal cells, such as astrocytes. While morphological changes in spinal astrocytes in relation to onset and progression of chronic pain have been well characterized, little is known about their dynamic activity patterns and how they relate to neuronal spiking or sex-specific immune responses. Historically, technical challenges have prevented such measurements in preclinical animal models under naturalistic conditions. The recent development of two-photon and miniaturized one-photon imaging approaches has enabled real-time measurement of cellular calcium activity in behaving mammals. This has provided first insights into how sensory information from mechanoreceptors and nociceptors in the skin acutely activates dorsal horn neurons and astrocytes. Using these cutting-edge imaging approaches in combination with computational, genetic, and behavioral techniques, the objective of this proposal is to define how astrocyte calcium activity changes in relation to neuropathic pain onset and progression, how its targeted manipulation influences neuronal and non-neuronal responses, and how it alters molecular signaling and animal behavior. The rationale for the proposed research is that by uncovering cellular and molecular mechanisms that contribute to pain onset or progression, new analgesic interventions can be devised. Three specific aims will be pursued: 1) Determine how astrocyte calcium excitation relates to neuropathic pain under naturalistic conditions; 2) Determine how inhibition of astrocyte calcium excitation modulates normal and aberrant sensory processing, and 3) Determine molecular pathways involved in astrocyte calcium excitation-mediated modulation of normal and aberrant sensory processing. In summary, this work will uncover how changes in astrocyte activity contribute to neuropathic pain on molecular, cellular, and behavioral levels. It will extend current models of how non-neuronal cells contribute to persistent pain specifically and CNS function broadly.

项目概要慢性疼痛是许多疾病的标志，包括神经和脊髓损伤。当前的疼痛管理的主要方法包括镇痛药和麻醉药，尽管它们的效果不佳，但仍使用这些治疗方法不确定的功效和已知的副作用。更安全、更有效的疼痛管理方法是迫切需要，但基础研究的知识差距阻碍了其开发和转化新的治疗方法。为了加速这一过程，加深对细胞和分子基础的理解需要疼痛信号。脊髓是重要的信号枢纽，参与传递疼痛相关信息周围器官和大脑之间的信号。作为中枢感觉统合的第一个部位神经系统（CNS），它在中枢敏化中起着重要作用。很多注意力都集中在有助于此过程的神经元细胞类型和电路。然而，人们对它的了解却少之又少非神经元细胞（例如星形胶质细胞）的贡献。虽然脊髓星形胶质细胞的形态变化慢性疼痛的发生和进展的关系已得到很好的表征，但对其的了解甚少动态活动模式以及它们与神经元尖峰或性别特异性免疫反应的关系。从历史上看，技术挑战阻碍了在临床前动物模型中进行此类测量自然条件。双光子和小型化单光子成像的最新进展该方法已经能够实时测量行为哺乳动物的细胞钙活性。这有首次深入了解皮肤中机械感受器和伤害感受器的感觉信息如何敏锐地表达出来激活背角神经元和星形胶质细胞。结合使用这些尖端成像方法通过计算、遗传和行为技术，该提案的目标是定义星形胶质细胞如何钙活性的变化与神经性疼痛的发作和进展有关，及其如何有针对性的操纵影响神经元和非神经元反应，以及它如何改变分子信号传导和动物行为。拟议研究的基本原理是通过揭示细胞和分子机制导致疼痛发作或进展，可以设计新的镇痛干预措施。三个具体目标将目标：1) 确定自然条件下星形胶质细胞钙兴奋与神经病理性疼痛的关系状况; 2) 确定星形胶质细胞钙兴奋的抑制如何调节正常和异常的感觉处理，3) 确定星形胶质细胞钙激发介导的分子途径正常和异常感觉处理的调节。总之，这项工作将揭示如何改变星形胶质细胞活性在分子、细胞和行为水平上导致神经性疼痛。它将延长目前关于非神经元细胞如何具体导致持续性疼痛以及中枢神经系统如何广泛发挥功能的模型。