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.

项目摘要慢性疼痛是许多疾病疾病的标志，包括神经和脊髓损伤。当前的疼痛管理的支柱包括镇痛药和麻醉药，尽管如此不确定的功效和已知副作用。疼痛管理的更安全，更有生产力的方法是迫切需要，但是基础研究中的知识差距阻碍了新颖的治疗方法。为了加速这一过程需要疼痛信号。脊髓是与疼痛相关的关键信号集线器外围器官和大脑之间的信号。作为中央感官集成的第一个站点神经系统（CNS），它在中央敏化中起着至关重要的作用。很多关注都集中在有助于此过程的神经元细胞类型和电路。但是，关于非神经元细胞的贡献，例如星形胶质细胞。而脊柱星形胶质细胞的形态变化与慢性疼痛的发作和进展有关的关系已经很好，对他们的动态活性模式及其与神经元尖峰或性别特异性免疫反应的关系。从历史上看，技术挑战阻止了临床前动物模型中的这种测量自然条件。最近的两光子和微型化的单光子成像的发展方法已实现了行为哺乳动物中细胞钙活性的实时测量。这就是首先洞悉了皮肤中的机械感受器和伤害感受器的感觉信息如何敏锐激活背角神经元和星形胶质细胞。组合使用这些尖端的成像方法通过计算，遗传和行为技术，该提案的目的是定义星形胶质细胞钙活性与神经性疼痛发作和进展的关系变化，其目标操纵如何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。拟议研究的理由是，通过发现细胞和分子机制可以设计出新的镇痛干预措施。三个具体目标将被追捕：1）确定星形胶质细胞钙激发与自然主义下的神经性疼痛之间的关系状况; 2）确定星形胶质细胞钙激发的抑制如何调节正常和异常的感觉处理，3）确定与星形胶质细胞钙兴奋介导的分子途径调节正常和异常的感觉处理。总而言之，这项工作将发现如何变化星形胶质细胞活性会导致分子，细胞和行为水平上的神经性疼痛。它将扩展当前非神经细胞如何对持续性疼痛的贡献以及CNS的功能广泛作用的当前模型。