Role of the TRPV1 channel in myocardial salvage from ischemia-reperfusion injury

项目摘要 应聘者：我是一名麻醉师，希望成为一名临床科学家。我感兴趣 检测瞬时受体香草醛通道（TRPV 1）在缺血心肌挽救中的作用， 再灌注损伤作为一名临床麻醉师，我觉得我有一套独特的技能来研究这种特殊的， 在基础科学实验室里解决相关的临床问题。我目前的研究方向是一个逻辑 继续我以前关于心肌缺血再灌注损伤的基础科学研究， 我的临床训练很不错然而，距离我上次强化基础科学训练已经过去5年了， 在配体诱导的心脏保护，所以我的直接目标是获得额外的研究培训，在先进的 分子生物学技术和重点职业发展，以过渡到一个独立的 调查员额外的研究和职业培训将是无价的，并让我能够回答相关的问题 这些问题我无法以其他方式来研究。这项工作，在这个奖项的支持下，将提供一个基础， 建立一个职业生涯作为教师，临床医生和麻醉学的基础科学家。 培训环境：斯坦福大学拥有世界一流的职业发展环境， 执行和学习新的，前沿的研究。斯坦福大学致力于我作为一名临床医生的发展 科学家，我提议对心血管医学院成员进行培训就证明了这一点 研究所，麻醉学系，化学与系统生物学系，我 导师（Daria Mochly-Rosen博士）、共同导师（Rona Giffard博士和大卫约曼斯博士）及其实验室 成员我组建了一个咨询团队，他们拥有多学科的研究专业知识和翻译技能。 研究，蛋白质化学和生物化学，心肌和神经元缺血再灌注损伤和疼痛 research.研究职业发展的关键因素包括提高我对蛋白质的知识 生物化学，蛋白质-蛋白质相互作用和疼痛信号传导的分子机制。我也会得到 在基于细胞的技术和小分子药物开发和设计方面的额外培训。 研究：辣椒通过辣椒素化合物产生辛辣的味道，辣椒素反过来也会释放出 内啡肽（这可能是我们喜欢辛辣食物的原因）。激活辣椒素敏感通道， 被称为瞬时受体电位香草素1（TRPV 1），可能不仅仅是疼痛和随后的信号 荣幸TRPV 1可以激活信号通路，减少缺氧对心脏的损伤 （局部缺血）心脏病发作期间。这可能表明胸痛（心绞痛）实际上是一种自然途径， 防止心脏病发作伤害。 TRPV 1激活产生的疼痛感觉是否与保护心脏病发作的途径有关？ 糖尿病增加心脏病发作的心血管风险，减少TRPV 1表达。糖尿病患者也 心脏病发作时没有症状或没有疼痛没有疼痛（TRPV 1激活），是否没有获得器官 保护？ 疼痛和保护之间的联系也是重要的研究，因为药物减少疼痛， 阻断TRPV 1通道的药物正在临床试验中。在本提案中，我将展示TRPV 1通道如何减少 心脏病发作造成的伤害通过研究TRPV 1糖基化（Aim 1)其次，蛋白激酶C（PKC）磷酸化（Aim 2），减轻心肌细胞损伤。然后我将 检查手术室中常用的药物，阿片类药物和挥发性麻醉剂，是否需要 TRPV 1减少缺血-再灌注损伤的损伤（目的3）。我还将确定是否在糖尿病 阿片类药物和挥发性麻醉剂对心脏病发作的保护作用的丧失可以通过改善 TRPV 1敏感性（目标4）。总之，这些研究将确定胸痛和心脏病发作损伤是如何 以及阿片类药物和挥发性麻醉剂如何通过TRPV 1激活启动通路， 心脏病发作受伤。

Project Summary Candidate: I am an anesthesiologist that desires a career as a clinician scientist. I am interested in examining the role of the transient receptor vanilliod channel (TRPV1) in myocardial salvage from ischemia- reperfusion injury. As a clinical anesthesiologist, I feel I have a skill set unique to studying this specific and pertinent clinical question in the basic science laboratory. My current research direction is a logical continuation from my previous basic science research regarding myocardial ischemia-reperfusion injury and compliments my clinical training. However, 5 years have passed since my last intensive basic science training in ligand-induced cardioprotection, so my immediate goal is to obtain additional research training in advanced molecular biology techniques and focused career development in order to transition to an independent investigator. Additional research and career training will be invaluable and allow me to answer pertinent questions that I could not examine otherwise. This work, with support by this award, will provide a foundation to establish a career as a teacher, clinician and a basic scientist in Anesthesiology. Training Environment: Stanford has an outstanding world-class environment for career development and to perform and learn novel, cutting edge research. Stanford is committed to my development as a clinician scientist, as evident by my proposed training from members in the School of Medicine, the Cardiovascular Research Institute, the Department of Anesthesiology, Department of Chemical and Systems Biology, my mentors (Dr. Daria Mochly-Rosen), co-mentors (Dr. Rona Giffard and Dr. David Yeomans) and their lab members. I assembled an advisory team with multidisciplinary research expertise and skills in translational research, protein chemistry and biochemistry, myocardial and neuronal ischemia-reperfusion injury and pain research. Key elements for research career development include enhancing my knowledge of protein biochemistry, protein-protein interactions and the molecular mechanisms of pain signaling. I will also obtain additional training in cellular-based techniques and small molecule drug development and design. Research: Chili peppers produce their hot spicy taste by the compound capsaicin, which in turn also releases endorphins (a probable reason why we are fond of spicy food). Activation of the capsaicin-sensitive channel, known as the transient receptor potential vanilloid 1 (TRPV1), may signal more than just pain and subsequent pleasure. TRPV1 may activate a signaling pathway which reduces injury from a lack of oxygen to the heart (ischemia) during a heart attack. This may suggest that the chest pain (angina) actually is a natural pathway to protect from heart attack injury. Is the pain sensation generated by TRPV1 activation linked to a pathway which protects from heart attacks? Diabetes, which increases cardiovascular risk for a heart attack, reduces TRPV1 expression. Diabetics also have heart attacks that are silent or painless. With no pain (TRPV1 activation), is there no gain of organ protection? The connection between pain and protection is also important to study because drugs to reduce pain by blocking the TRPV1 channel are in clinical trials. In this proposal, I will show how the TRPV1 channel reduces injury from a heart attack. I will determine the molecular basis by studying whether TRPV1 glycosylation (Aim 1) and secondly, protein kinase C epsilon (PKC¿) phosphorylation (Aim2), reduce heart cell injury. I will then examine whether agents commonly given in the operating room, opioids and volatile anesthetics, require TRPV1 to reduce damage from ischemia-reperfusion injury (Aim 3). I also will determine whether in diabetes the loss of protection from a heart attack by opioids and volatile anesthetics can be reversed by improving TRPV1 sensitivity (Aim 4). Together, these studies will identify how chest pain and heart attack injury are connected and how opioids and volatile anesthetics initiate a pathway by TRPV1 activation which reduces heart attack injury.