Cellular Physiology of Sensory Ion Channels

感觉离子通道的细胞生理学

基本信息

批准号：
7452518
负责人：
David Julius
金额：
$ 33.33万
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：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452518
关键词：
Address Afferent Neurons Agonist Amplifiers Analgesics Arthritis Aspirin Biochemical Biological Factors Bradykinin Calcium Caliber Capsaicin Cell Surface Receptors Cell physiology Cells Chemical Agents Chemicals Class Computer information processing Condition Deer Detection Development Diabetic Neuropathies Environment Enzymes Esthesia Event Fractionation Goals Hand Heating Histamine Hyperalgesia Image Inflammatory Ion Channel Irritants Isothiocyanates Laboratories Light Mediating Menthol Methods Molecular Molecular Genetics Molecular Target Morphine Mus Mustard Plant Nervous system structure Neurogenic Inflammation Neurons Nociceptors Opioid Receptor Pain Peripheral Physiological Plants Process Production Psychophysiology Research Personnel Role Sensory Sensory Nerve Endings Sensory Process Serotonin Shock Signal Transduction Squirrel Stimulus Syndrome System TRP channel TRPA1 Channel Testing Trigeminal System Viral allyl isothiocyanate chemical genetics design expression cloning in vivo insight irritation mustard oil novel patch clamp programs receptor receptor coupling receptor operated channel research study response sanshool sensory stimulus somatosensory tool ward

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how our nervous system detects and processes information in our environment and transduces such environmental stimuli into electrochemical events. Our approach is to exploit the pharmacological power of natural plant products, specifically those that elicit irritation or discomfort, to uncover novel signaling mechanisms involved in the detection of noxious stimuli by neurons of the somatosensory nervous system. Indeed, this approach has proven to be extremely fruitful in the discovery and analysis of cell surface receptors and enzymes that are important for the detection and modulation of pain-producing stimuli, as illustrated by the use of plant-derived products such as aspirin, morphine, capsaicin, and menthol to discover cycloogenases, opiate receptors, and thermosensitive TRP channels, respectively. A major focus of this application is to determine how pungent isothiocyanate compounds from mustard plants (such as wasabi) excite sensory neurons by activating TRPA1, an excitatory channel on primary sensory neurons. It is currently unknown how these agents serve as selective agonists for the TRPA1 channel. We will use a combination of genetic, chemical, and electrophysiological methods to address this question, answers to which should provide significant insight into endogenous mechanisms that promote the activation and/or modulation of TRPA1. In addition to serving as a "wasabi receptor", TRPA1 may contribute to the mechanism whereby inflammatory products, such as bradykinin, histamine, or serotonin excite sensory neurons. Thus, another of our aims is to use cultured sensory neurons from normal and TRPA1-deficient mice to determine whether TRPA1 contributes to these excitatory actions and, if so, what cellular signaling mechanisms underlie this process. Finally, we are also proposing to examine effects of other natural products on cultured sensory neurons with the aim of developing novel pharmacological probes with which to discover or characterize important cellular signaling mechanisms that contribute to the detection or modulation of sensory stimuli. These studies may stimulate the design and development of novel analgesic agents for treating peripheral pain syndromes, such as arthritis or viral and diabetic neuropathies.

描述（由申请人提供）：该提案的长期目标是了解我们的神经系统如何检测和处理环境中的信息并将此类环境刺激转化为电化学事件。我们的方法是利用天然植物产品的药理作用，特别是那些引起刺激或不适的植物产品，以揭示体感神经系统神经元检测有害刺激所涉及的新信号传导机制。事实上，这种方法已被证明在发现和分析细胞表面受体和酶方面非常富有成效，这些受体和酶对于检测和调节产生疼痛的刺激非常重要，如阿司匹林、吗啡等植物衍生产品的使用所证明的那样、辣椒素和薄荷醇，分别发现环化酶、阿片受体和热敏 TRP 通道。该应用的主要重点是确定来自芥菜植物（例如芥末）的刺激性异硫氰酸酯化合物如何通过激活 TRPA1（初级感觉神经元的兴奋通道）来兴奋感觉神经元。目前尚不清楚这些药物如何作为 TRPA1 通道的选择性激动剂。我们将结合使用遗传、化学和电生理学方法来解决这个问题，这些问题的答案将为促进 TRPA1 激活和/或调节的内源性机制提供重要的见解。除了充当“芥末受体”之外，TRPA1 还可能有助于缓激肽、组胺或血清素等炎症产物刺激感觉神经元的机制。因此，我们的另一个目标是使用来自正常和 TRPA1 缺陷小鼠的培养感觉神经元来确定 TRPA1 是否有助于这些兴奋作用，如果是的话，该过程背后的细胞信号传导机制是什么。最后，我们还建议检查其他天然产物对培养的感觉神经元的影响，目的是开发新型药理学探针，用于发现或表征有助于检测或调节感觉刺激的重要细胞信号传导机制。这些研究可能会刺激用于治疗周围疼痛综合征（例如关节炎或病毒性和糖尿病性神经病）的新型镇痛剂的设计和开发。