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，希望成为临床科学家。我感兴趣的是 检测瞬时受体香草酸通道(TRPV1)在心肌缺血挽救中的作用 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个特定的和 基础科学实验室中的相关临床问题。我目前的研究方向是合乎逻辑的 延续了我以前关于心肌缺血再灌注损伤的基础科学研究 称赞我的临床训练。然而，距离我最后一次强化基础科学训练已经过去了5年 在配体诱导的心脏保护方面，所以我的直接目标是获得更多的高级研究培训 分子生物学技术和专注的职业发展才能过渡到独立 调查员。更多的研究和职业培训将是无价的，让我能够回答相关的问题 以其他方式我无法研究的问题。这项工作，在该奖项的支持下，将为 建立自己的职业生涯，成为麻醉学的教师、临床医生和基础科学家。 培训环境：斯坦福拥有卓越的世界级职业发展环境和 进行和学习新奇的、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，正如我在医学院心血管学院成员提出的培训所证明的那样 研究所，麻醉学系，化学与系统生物学系，我的 导师(Daria Mochly-Rosen博士)、共同导师(Rona Giffard博士和David Yeomans博士)及其实验室 会员。我组建了一个具有多学科研究专长和翻译技能的顾问团队 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 研究。研究生涯发展的关键要素包括增强我对蛋白质的知识 生物化学、蛋白质-蛋白质相互作用和疼痛信号的分子机制。我也会拿到 细胞技术和小分子药物开发和设计方面的额外培训。 研究：辣椒通过复合辣椒素产生辛辣味道，辣椒素反过来也会释放出来 内啡肽(这可能是我们喜欢辛辣食物的一个原因)。辣椒素敏感通道的激活， 被称为瞬时受体电位香草素1(TRPV1)的信号可能不仅仅是疼痛和随后的 很高兴见到你。TRPV1可以激活一条信号通路，减轻缺氧对心脏的损伤 (缺血)在心脏病发作期间。这可能表明胸痛(心绞痛)实际上是一种自然途径 保护心脏免受心脏病发作的伤害。 TRPV1激活产生的痛感是否与预防心脏病发作的途径有关？ 糖尿病会增加心脏病发作的心血管风险，减少TRPV1的表达。糖尿病患者也 无痛或无痛的心脏病发作。没有疼痛(TRPV1激活)，器官就没有收获吗？ 保护？ 疼痛和保护之间的联系也值得研究，因为药物通过以下方式减轻疼痛 阻断TRPV1通道正在进行临床试验。在本提案中，我将展示TRPV1通道如何减少 心脏病发作造成的伤害。我将通过研究TRPV1糖基化(AIM)来确定分子基础 1)和第二，蛋白激酶C epsilon(PKC？)磷酸化(AIM2)，减轻心肌细胞损伤。那我会的 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 TRPV1减少缺血再灌注损伤的损伤(目标3)。我还将确定糖尿病患者是否 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 TRPV1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激活TRPV1启动一条途径，从而减少 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.