ASIC Channels and Pain

ASIC 通道和痛点

• 批准号: 8420118
• 负责人: David Julius
• 金额: $ 38.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420118
• 关键词: ASIC channel; Accounting; Acidosis; Acids; Acute Pain; Address; Afferent Neurons; Agonist; Amino Acid Sequence; Animals; Applied Genetics; Arthritis; Attention; Behavior; Behavioral Assay; Biochemical; Chronic; Chronic inflammatory pain; Detection; Development; Drops; Elements; Esthesia; Family; Fiber; Gene Targeting; Genes; Goals; Hyperalgesia; Hypersensitivity; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Ion Channel; Ischemia; Label; Life; Ligands; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Membrane; Methods; Mus; Myocardium; Nerve; Nerve Fibers; Neurogenic Inflammation; Neurons; Nociception; Nociceptors; Oocytes; Pain; Pattern; Peptide Sequence Determination; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Play; Population; Preparation; Process; Property; Proteins; Protons; Rana; Recruitment Activity; Relative (related person); Reporter; Role; Screening procedure; Sensitivity and Specificity; Sensory Ganglia; Series; Signal Transduction; Site; Skeletal Muscle; Skin; Snakes; Somatosensory Receptor; Spinal Cord; Stimulus; Syndrome; System; Systems Analysis; TRPV1 gene; Temperature; Therapeutic; Therapeutic Agents; Time; Tissue Extracts; Tissues; Touch sensation; Toxin; afferent nerve; allodynia; cellular imaging; chronic pain; extracellular; imaging modality; in vivo; inflammatory pain; injured; insight; interest; knockout gene; member; nerve injury; neurochemistry; neuronal cell body; novel; novel therapeutics; promoter; protein complex; receptive field; receptor; response; sensor; somatosensory; tool; tumor growth

DESCRIPTION (provided by applicant): Nociception is the process whereby primary afferent somatosensory neurons recognize and respond to noxious stimuli. In addition to initiating acute pain responses, nociceptor activation can produce local inflammation leading to pain hypersensitivity. Tissue acidosis (i.e. reduction in local pH) is an important hallmark of this response, and is associated with a range of physiological insults, such as infection, ischemia, tumor growth, and arthritis. Indeed, extracellular protons enhance excitability of primary afferent nociceptors, thereby producing acute pain and/or pain hypersensitivity. Members of the acid sensing ion channel (ASIC) family are believed to play important roles in nociception and pain by functioning as sensors for extracellular protons. For example, the ASIC3 subtype likely accounts for ischemic pain associated with large, rapidly inactivating proton-evoked currents in neurons that innervate skeletal or cardiac muscle. However, additional roles for ASIC channels in nociception have remained enigmatic for a variety of reasons. First, a dearth of pharmacological tools has made it difficult to manipulate these channels in vivo. Second, mice lacking specific ASIC channel subtypes have failed to revealed clear or robust phenotypes in regard to acid-evoked pain or other aspects of nociception. Third, a comprehensive analysis of ASIC channel expression and localization - which is critical to deciphering physiological roles for these channels in nociception and pain - remains incomplete. Finally, some ASIC subtypes (e.g. ASIC2a) respond only to extreme extracellular acidosis (pH < 5), suggesting the existence of other endogenous modulators for these channels that may be produced under pathophysiological conditions of tissue injury and/or chronic inflammation. The goal of this proposal is to address these and other questions by applying genetic, physiologic, and biochemical methods to develop a comprehensive view of ASIC subtype function, pharmacology, and expression in the somatosensory system. The specific aims are to (i) develop a comprehensive map of ASIC channel expression using gene targeted reporter mice to visualize ASIC-positive nerve fibers with exquisite sensitivity and fidelity; (ii) characterize functional properties of ASIC-expressing sensory neurons and nerve fibers from these genetically-labeled mice using a range of electrophysiological and live-cell imaging methods; (iii) screen for novel endogenous ASIC modulators in extracts of normal and injured tissues using a range of biochemical, functional, and behavioral assays. Together, these aims will address important unresolved questions concerning ASIC function as key steps toward the rational development of novel therapeutic agents that target a range of chronic inflammatory pain syndromes. PUBLIC HEALTH RELEVANCE: This project investigates a family of membrane ion channels that detect tissue acidosis and activate nerve fibers that generate pain signals. Results from these studies will expand our understanding of an important class of ion channels that contribute to pain sensation, thereby illuminating therapeutic strategies (such as novel drugs) for treating chronic pain syndromes associated with arthritis, inflammatory bowel disease, cancer, and other forms of tissue and nerve injury.

描述（由申请人提供）：伤害感受是初级传入体感神经元识别并响应有害刺激的过程。除了引发急性疼痛反应外，伤害感受器激活还可产生局部炎症，导致疼痛过敏。组织酸中毒（即局部 pH 值降低）是这种反应的一个重要标志，并且与一系列生理损伤有关，例如感染、缺血、肿瘤生长和关节炎。事实上，细胞外质子增强初级传入神经的兴奋性 伤害感受器，从而产生急性疼痛和/或疼痛过敏。酸传感离子通道 (ASIC) 家族的成员被认为通过充当细胞外质子的传感器，在伤害感受和疼痛中发挥重要作用。例如，ASIC3 亚型可能是与支配骨骼或心肌的神经元中大量、快速失活的质子诱发电流相关的缺血性疼痛的原因。然而，由于多种原因，ASIC 通道在伤害感受中的其他作用仍然是个谜。首先，药理学工具的缺乏使得在体内操纵这些通道变得困难。其次，缺乏特定 ASIC 通道亚型的小鼠未能在酸引起的疼痛或伤害感受的其他方面表现出清晰或稳健的表型。第三，对 ASIC 通道表达和定位的全面分析 - 这对于破译生理作用至关重要 这些伤害感受和疼痛的通道仍然不完整。最后，一些 ASIC 亚型（例如 ASIC2a）仅对极端细胞外酸中毒（pH < 5）有反应，这表明这些通道存在其他内源性调节剂，这些调节剂可能在组织损伤和/或慢性炎症的病理生理条件下产生。本提案的目标是通过应用遗传、生理和生化方法来解决这些问题和其他问题，以全面了解 ASIC 亚型功能、药理学和体感系统中的表达。具体目标是 (i) 使用基因靶向报告小鼠开发 ASIC 通道表达的综合图谱，以极高的灵敏度和保真度可视化 ASIC 阳性神经纤维； (ii) 使用一系列电生理学和活细胞成像方法表征这些基因标记小鼠的表达 ASIC 的感觉神经元和神经纤维的功能特性； (三) 使用一系列生化、功能和行为测定，在正常和受损组织的提取物中筛选新型内源 ASIC 调节剂。总之，这些目标将解决有关 ASIC 功能的重要未解决问题，作为合理开发针对一系列慢性炎症疼痛综合征的新型治疗药物的关键步骤。 公共健康相关性：该项目研究了一系列膜离子通道，这些通道可检测组织酸中毒并激活产生疼痛信号的神经纤维。这些研究的结果将扩大我们对一类有助于痛觉的重要离子通道的理解，从而阐明治疗策略（例如新药物） 治疗与关节炎、炎症性肠病、癌症以及其他形式的组织和神经损伤相关的慢性疼痛综合征。