Capsaicin receptor subtypes in pain transduction

疼痛传导中的辣椒素受体亚型

基本信息

批准号：
8133166
负责人：
MARK A SCHUMACHER
金额：
$ 7.73万
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：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133166
关键词：
Acute Address Adverse effects Afferent Neurons Area Behavioral Binding Binding Sites Boxing Burn injury Calcium Capsaicin Cells Chili Pepper Clinical Collaborations Data Development EMSA Esthesia Family Figs - dietary Genetic Transcription Hyperalgesia Image In Vitro Individual Inflammation Inflammation Mediators Inflammatory Injury Ion Channel Link Measurement Mediating Medical Messenger RNA Molecular Profiling Mus N-terminal Nerve Growth Factors Nervous system structure Neurons Nociception Nociceptors Pain Pain management Peripheral Persistent pain Physiological Play Production Promoter Regions Property Proteins Quality of life RNA RNA Splicing Rattus Regulation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Seminal Site Sp1 Transcription Factor Stimulus System TRPV1 gene Techniques Testing Thermal Hyperalgesias Tissues Transcriptional Regulation Variant afferent nerve base capsaicin receptor cell type chromatin immunoprecipitation chronic pain in vivo inflammatory pain inhibitor/antagonist knock-down patch clamp promoter protein expression public health relevance receptor response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Pain, one of the oldest medical problems still remains an immense clinical challenge. Our ability to effectively treat acute and especially chronic painful conditions often causes other unwanted side-effects that degrade the quality of life. TRPV1, also known as the capsaicin receptor, has been at the forefront of research focused on the development of new strategies to treat chronic painful conditions that arise from inflammation. TRPV1 is expressed in primary afferent nociceptors (specialized sensory neurons) that detect painful stimuli and its expression is increased in these nerve cells under conditions of inflammation. Increased levels of TRPV1 appear to drive the development of persistent pain and hyperalgesia. Surprisingly, little is known about what controls the production of TRPV1 in the nervous system under normal or inflammatory conditions. The current project is focused on: 1) Understanding how inflammatory mediators released at the site of injury, such as Nerve Growth Factor (NGF), increase TRPV1 production under conditions of inflammation. We have recently demonstrated that NGF positively regulates the transcriptional control regions in the rat TRPV1 gene. Based on additional data, we now propose to study a link between the Sp1- like family of transcription factors and NGF / inflammation mediated increases in TRPV1 dependent pain. 2) Another area of study is the regulation of TRPV1 expressed activity through its co-expression with other TRPV1 splice variants. Previously, we identified a TRPV1 splice variant (VR.5'sv) that when co-expressed, blocks TRPV1 activation to noxious stimuli in vitro. We now propose to study the physiologic consequence of VR.5'sv and other TRPV1 splice variants in individual sensory neurons. By studying the individual response properties of nociceptive neurons and matching these responses to a molecular signature of splice variant expression, we will determine the role of TRPV1 splice variants in the control of nociceptor activation and pain transduction. PUBLIC HEALTH RELEVANCE: The basis for chronic pain arising from inflammatory conditions is poorly understood. The receptor that detects the burning sensation to pungent hot chili peppers is important for maintaining inflammatory pain in sensory nerves. We are studying a way to reduce or turn off the production of this receptor in sensory nerves as a way to control the pain from chronic peripheral inflammation.

描述（由申请人提供）：疼痛，最古老的医学问题之一仍然是巨大的临床挑战。我们有效治疗急性，尤其是慢性疼痛状况的能力通常会引起其他不必要的副作用，从而降低生活质量。 TRPV1，也称为辣椒素受体，一直处于研究的最前沿，着重于制定新策略，以治疗炎症引起的慢性疼痛状况。 TRPV1在炎症条件下在这些神经细胞中检测到疼痛刺激的原发性伤害感受器（专门的感觉神经元）中表达。 TRPV1水平的增加似乎促进了持续性疼痛和痛风的发展。令人惊讶的是，关于在正常或炎症条件下神经系统中TRPV1产生的是什么知之甚少。当前项目的重点是：1）了解炎症部位释放的炎症介质如何在炎症条件下增加TRPV1的产生。我们最近证明，NGF积极调节大鼠TRPV1基因中的转录控制区域。基于其他数据，我们现在建议研究SP1类转录因子家族与NGF /炎症介导的TRPV1依赖性疼痛的增加之间的联系。 2）研究的另一个领域是通过与其他TRPV1剪接变体共表达TRPV1表达活性。以前，我们确定了TRPV1剪接变体（VR.5'SV），即共表达时，在体外将TRPV1激活阻塞至有害刺激。现在，我们建议研究单个感觉神经元中VR.5'SV和其他TRPV1剪接变体的生理后果。通过研究伤害性神经元的个体反应特性，并将这些响应与剪接变体表达的分子特征相匹配，我们将确定TRPV1剪接变体在控制伤害感受器激活和疼痛转导的作用。公共卫生相关性：炎症状况引起的慢性疼痛的基础知之甚少。检测到刺激性热辣椒辣椒的受体对于保持感觉神经的炎症性疼痛很重要。我们正在研究一种方法来减少或关闭感觉神经中该受体的产生，以控制慢性外周炎症的疼痛。