ASIC Channels and Pain

ASIC 通道和痛点

• 批准号: 9062527
• 负责人: David Julius
• 金额: $ 37.23万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062527
• 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; Cells; Chronic; Chronic inflammatory pain; Detection; Development; Drops; Electrophysiology (science); Elements; Esthesia; Family; Fiber; Gene Targeting; Genes; Goals; Hyperalgesia; Hypersensitivity; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Ion Channel; Ischemia; Label; 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; Pharmacology; Phenotype; Physiological; Physiology; Play; Population; Preparation; Process; Property; Proteins; Protons; Rana; Recruitment Activity; Reporter; Role; 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; chronic pain; extracellular; imaging modality; in vivo; inflammatory pain; injured; insight; interest; knockout gene; live cell imaging; member; nerve injury; neurochemistry; novel; novel therapeutics; promoter; protein complex; receptive field; receptor; response; screening; 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.

描述（由申请人提供）：伤害感觉是初级传入体感觉神经元识别和响应有害刺激的过程。除了引发急性疼痛反应外，伤害感受器的激活还会产生局部炎症，导致疼痛超敏反应。组织酸中毒（即局部pH值降低）是这种反应的一个重要标志，并与一系列生理损伤有关，如感染、缺血、肿瘤生长和关节炎。事实上，细胞外质子增强了初级传入的兴奋性