Capsaicin receptor subtypes in pain transduction

疼痛传导中的辣椒素受体亚型

• 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
• 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

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，仍然是一个巨大的临床挑战。我们有效治疗急性疼痛，尤其是慢性疼痛的能力往往会导致其他不必要的副作用，降低生活质量。TRPV1，也被称为辣椒素受体，一直处于研究的前沿，专注于开发治疗炎症引起的慢性疼痛的新策略。TRPV1在检测疼痛刺激的初级传入伤害感受器（专门的感觉神经元）中表达，在炎症条件下，其表达在这些神经细胞中增加。升高的TRPV1水平似乎推动了持续性疼痛和痛觉过敏的发展。令人惊讶的是，在正常或炎症条件下，是什么控制神经系统中TRPV1的产生，我们知之甚少。目前的项目重点是：1)了解在炎症条件下损伤部位释放的炎症介质，如神经生长因子（NGF）如何增加TRPV1的产生。我们最近证明了NGF正调控大鼠TRPV1基因的转录控制区域。基于其他数据，我们现在建议研究Sp1样转录因子家族与NGF /炎症介导的TRPV1依赖性疼痛增加之间的联系。2)另一个研究领域是通过TRPV1与其他TRPV1剪接变体的共表达来调节TRPV1表达活性。在此之前，我们发现了TRPV1剪接变体（VR.5’sv），当它在体外共表达时，可以阻断TRPV1对有害刺激的激活。我们现在建议研究vr5 'sv和其他TRPV1剪接变体在单个感觉神经元中的生理后果。通过研究痛觉神经元的个体反应特性，并将这些反应与剪接变体表达的分子特征相匹配，我们将确定TRPV1剪接变体在控制痛觉感受器激活和疼痛转导中的作用。公共卫生相关性：炎症引起的慢性疼痛的基础尚不清楚。感知辛辣辣椒灼热感的受体对于维持感觉神经的炎症性疼痛很重要。我们正在研究一种减少或关闭感觉神经中这种受体的产生的方法，以控制慢性外周炎症引起的疼痛。