ASIC Channels and Pain

ASIC 通道和痛点

基本信息

批准号：
8661323
负责人：
David Julius
金额：
$ 36.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8661323
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 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 screening sensor somatosensory tool tumor growth

项目摘要

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）：伤害感受是主要传入的体感神经元识别并应对有害刺激的过程。除了引发急性疼痛反应外，伤害感受器的激活还会引起局部炎症，导致疼痛超敏反应。组织酸中毒（即减少局部pH值）是这种反应的重要标志，与一系列生理损伤有关，例如感染，缺血，肿瘤生长和关节炎。实际上，细胞外质子增强了主要传入的兴奋性伤害感受器，从而产生急性疼痛和/或疼痛超敏反应。据信，酸性传感离子通道（ASIC）家族的成员通过作为细胞外质子的传感器发挥作用在伤害感受和疼痛中起着重要作用。例如，ASIC3亚型可能解释了缺血性疼痛与神经支配骨骼或心脏肌肉的神经元中大型，迅速失活的质子诱发电流有关。但是，由于多种原因，ASIC通道在伤害感受中的其他作用仍然存在。首先，缺乏药理学工具使在体内操纵这些渠道变得困难。其次，缺乏特定ASIC通道亚型的小鼠在酸诱发的疼痛或伤害感受方面未能揭示出明确或健壮的表型。第三，对ASIC渠道表达和本地化的综合分析 - 这对于破译生理作用至关重要伤害性和疼痛中的这些通道仍然不完整。最后，一些ASIC亚型（例如ASIC2A）仅对极端的细胞外酸中毒（pH <5）反应，这表明在组织损伤和/或慢性炎症的病理生理条件下可能存在其他内源性调节剂。该提案的目的是通过应用遗传，生理和生化方法来解决这些问题和其他问题，以在体感系统中对ASIC亚型功能，药理学和表达进行全面观察。具体目的是（i）使用靶向记者小鼠的基因靶向小鼠来开发一张全面的ASIC通道表达图，以使ASIC阳性神经纤维具有精致的灵敏度和忠诚度；（ii）使用一系列电生理学和活细胞成像方法来表征这些遗传标记小鼠的表达ASIC表达感觉神经元和神经纤维的功能特性；（iii）使用一系列生化，功能性和行为测定法进行正常组织和受伤组织提取物中新型内源性ASIC调节剂的筛选。总之，这些目标将解决有关ASIC功能的重要尚未解决的问题，这是针对针对一系列慢性炎性疼痛综合征的新型治疗剂的合理发展的关键步骤。