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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：
8312645
负责人：
MARK A SCHUMACHER
金额：
$ 26.5万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8312645
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 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 abstracting afferent nerve base capsaicin receptor cell type chromatin immunoprecipitation chronic pain in vivo inflammatory pain inhibitor/antagonist knock-down patch clamp promoter protein expression receptor response transcription factor

项目摘要

Project Summary/Abstract 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.

项目总结/摘要疼痛，最古老的医学问题之一，仍然是一个巨大的临床挑战。我们有效治疗急性，尤其是慢性疼痛的能力，导致其他不必要的副作用，降低生活质量。TRPV 1，也称为作为辣椒素受体，一直处于研究的前沿，开发新的策略来治疗由以下原因引起的慢性疼痛炎症TRPV 1在初级传入伤害感受器（专门的感觉神经元）中表达。神经元），其在这些神经细胞中的表达增加在炎症的情况下。TRPV 1水平的增加似乎驱动了持续性疼痛和痛觉过敏的发展。令人惊讶的是，我们对控制TRPV 1在正常或炎症状态下神经系统中的产生条件当前项目的重点是：1）了解炎症如何在损伤部位释放的介质，如神经生长因子（NGF），在炎症条件下TRPV 1的产生。我们最近展示了 NGF正调控大鼠TRPV 1基因的转录控制区。基于额外的数据，我们现在建议研究Sp1样家族与转录因子和NGF /炎症介导的TRPV 1依赖性增加痛苦2)另一个研究领域是TRPV 1表达活性的调节，通过其表达的蛋白质来实现。与其他TRPV 1剪接变体共表达。之前，我们发现了一种TRPV 1 剪接变体（VR.5 ′ sv），当共表达时，阻断TRPV 1活化，体外刺激。我们现在建议研究VR.5 'sv的生理后果，其他TRPV 1剪接变异体在个别感觉神经元。通过研究个体伤害感受神经元的反应特性，并将这些反应与剪接变异体表达的分子特征，我们将确定TRPV 1的作用剪接变体在控制伤害感受器激活和疼痛转导中的作用。