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

描述（由申请人提供）：我是一名麻醉师，希望成为一名临床科学家。我感兴趣的是研究瞬时受体香草醛通道（TRPV 1）在心肌缺血再灌注损伤中的作用。作为一名临床麻醉师，我觉得我有一套独特的技能，可以在基础科学实验室研究这个具体而相关的临床问题。我目前的研究方向是我以前关于心肌缺血再灌注损伤的基础科学研究的逻辑延续，并补充了我的临床训练。然而，自从我上次在配体诱导的心脏保护方面进行密集的基础科学培训以来，已经过去了5年，因此我的近期目标是获得先进分子生物学技术和重点职业发展的额外研究培训，以便过渡到独立研究者。额外的研究和职业培训将是非常宝贵的，并允许我回答我无法研究的相关问题。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，可以进行和学习新颖的前沿研究。斯坦福大学致力于我作为临床科学家的发展，这一点可以从我在医学院、心血管研究所、麻醉学系、化学和系统生物学系的成员、我的导师（Daria Mochly-Rosen博士）、共同导师（Rona Giffard博士和大卫约曼斯博士）及其实验室成员的培训中得到证明。我组建了一个咨询团队，在转化研究，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方面具有多学科研究专业知识和技能。研究职业发展的关键因素包括提高我对蛋白质生物化学，蛋白质-蛋白质相互作用和疼痛信号分子机制的认识。我还将获得基于细胞的技术和小分子药物开发和设计的额外培训。调研：辣椒的辣味是由辣椒素产生的，辣椒素反过来也会释放内啡肽（这可能是我们喜欢辛辣食物的原因）。辣椒素敏感通道（称为瞬时受体电位香草酸1（TRPV 1））的激活可能不仅仅是疼痛和随后的快乐。TRPV 1可以激活信号通路，从而减少心脏病发作期间缺氧对心脏的损伤（缺血）。这可能表明，胸痛（心绞痛）实际上是一种保护心脏病发作的自然途径。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。糖尿病患者也有心脏病发作是无声的或无痛的。没有疼痛（TRPV 1激活），是否没有器官保护的增益？疼痛和保护之间的联系也很重要，因为通过阻断TRPV 1通道来减轻疼痛的药物正在临床试验中。在这个提案中，我将展示TRPV 1通道如何减少心脏病发作的伤害。我将通过研究TRPV 1糖基化（Aim 1）和蛋白激酶C β（PKC 5）磷酸化（Aim 2）是否减少心脏细胞损伤来确定分子基础。然后，我将研究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来减少缺血再灌注损伤的损伤（目的3）。我还将确定在糖尿病患者中，阿片类药物和挥发性麻醉剂对心脏病发作的保护作用是否可以通过提高TRPV 1的敏感性来逆转（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联系在一起的，以及阿片类药物和挥发性麻醉剂如何通过TRPV 1激活来启动一条减少心脏病发作损伤的途径。

DESCRIPTION (provided by applicant): 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 (PKC5) 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.