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Mechanisms of Heat Activation and Multimodal Functions of VR1 Receptor Channels

VR1受体通道的热激活机制和多模态功能

基本信息

批准号：
8073878
负责人：
FENG QIN
金额：
$ 7.5万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-30 至 2011-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Pain begins with transduction at peripheral nerve terminals of specialized sensory neurons called nociceptors. Understanding how these nociceptors respond to pain-producing stimuli is a key step towards understanding the biology of pain. This research concerns ion channels underlying nociception, in particular, the cloned vanilloid receptor TRPV1. Recent studies of the channel have shown a previously unsuspected level of complexity in its function and regulation and have implicated it in detection and integration of both exogenous noxious stimuli such as heat, vanilloids and acids and endogenous proinflammatory signals. The goal of the project is to determine, at the molecular level, how the receptor functions as a versatile noxious detector and integrator in response to various stimuli, using methods of single-channel electrophysiology combined with molecular biology. The first aim will focus on the mechanisms of the polymodal activation of the channel. Experiments are proposed to determine whether the heat sensitivity is required by other stimuli to activate the channel and how the stimuli of different modality interact within the receptor. The work will also develop allosteric models that unify the polymodal gating of the channel. The second objective is to investigate the structural basis of the polymodal activation. The study will examine to what extent the gating machinery for different stimuli are separated and will delineate the molecular domains specific to each stimulus and determine their functional mechanisms. The third aim concerns the desensitization and recovery of the channel. Experiments are proposed to quantify and establish the mechanisms of the depletion of phosphatidylinositol-45-bisphosphate (PIP2) caused by activation of TRPV1, and to elucidate the nature of the desensitized states. The proposed research will improve our knowledge of nociceptive sensory transduction and will benefit clinical advances in pain therapy, in particular, the search for analgesic drugs that have an entirely new mode of action and an unprecedented selectivity for nociceptors.

描述(申请人提供)：疼痛开始于周围神经末梢的特殊感觉神经元的转导，称为伤害性感受器。了解这些伤害性感受器如何对产生疼痛的刺激做出反应是了解疼痛生物学的关键一步。这项研究涉及伤害性感受的离子通道，特别是克隆的香草素受体TRPV1。最近对该通道的研究表明，它的功能和调控达到了前所未有的复杂程度，并涉及到对外部伤害性刺激(如热、香草素和酸)以及内源性促炎信号的检测和整合。该项目的目标是利用单通道电生理学和分子生物学相结合的方法，在分子水平上确定受体如何作为一个多功能的伤害性检测器和积分器来响应各种刺激。第一个目标将集中在通道多模式激活的机制上。实验是为了确定其他刺激是否需要热敏感性来激活通道，以及不同形式的刺激如何在感受器内相互作用。这项工作还将开发变构模型，以统一通道的多模式门控。第二个目标是探讨多峰激活的结构基础。这项研究将检验不同刺激的门控机制在多大程度上被分开，并将描绘出每个刺激特定的分子结构域，并确定它们的作用机制。第三个目标涉及通道的脱敏和恢复。为了定量和确定TRPV1激活导致磷脂酰肌醇-45-二磷酸(PIP2)耗竭的机制，并阐明这种失敏状态的性质。这项研究将提高我们对伤害性感觉转导的认识，并将有助于疼痛治疗的临床进展，特别是寻找具有全新作用模式和对伤害性感受器具有前所未有的选择性的止痛药。