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

TRPV1通道在缺血再灌注损伤心肌抢救中的作用

基本信息

批准号：
9088496
负责人：
Eric Richard Gross
金额：
$ 23.04万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088496
关键词：
Accident and Emergency department Acute myocardial infarction Advisory Committees Analgesics Anesthesiology Anesthetics Animals Award Basic Science Blood Vessels Capsaicin Cardiotonic Agents Cardiovascular system Cell Death Cell Survival Chemicals Chest Pain Chili Pepper Chronic Clinical Clinical Trials Coronary Artery Bypass Development Diabetes Mellitus Diet Doctor of Philosophy Drug Design Eating Elements Endorphins Environment Esthesia Event Faculty Food Foundations Goals Heart Heating Hyperglycemia Incidence Injury Interdisciplinary Study Ischemia Knowledge Laboratories Learning Ligands Link Mediator of activation protein Mentors Modification Molecular Molecular Biology Techniques Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Neurons Operating Rooms Operative Surgical Procedures Opioid Organ Organ Transplantation Oxygen Pain Pain Research Pain management Painless Pathway interactions Patients Peptides Peripheral Nervous System Diseases Pharmaceutical Preparations Phase Phosphorylation Physicians Post-Translational Protein Processing Postdoctoral Fellow Protein Biochemistry Protein Chemistry Reperfusion Injury Reperfusion Therapy Research Research Institute Research Personnel Research Training Risk Rodent Role Scientist Signal Pathway Signal Transduction Signaling Protein Stimulus Systems Biology Taste Perception Techniques Therapeutic Time Tissues Training Translational Research United States Vanilloid Work base cardiovascular risk factor career career development cell injury clinical practice design diabetic drug development experience glycosylation heart cell improved in vivo Model insight interest medical schools member myocardial infarct sizing novel novel therapeutics pain receptor pleasure prevent protein kinase C epsilon protein protein interaction receptor skills small molecule teacher

项目摘要

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.

项目概要候选人：我是一名麻醉师，希望成为一名我感兴趣的临床科学家。研究瞬时受体香草酸通道 (TRPV1) 在心肌缺血挽救中的作用作为一名临床麻醉师，我觉得我拥有研究这一特定和特定领域的独特技能。我目前的研究方向是基础科学实验室的相关临床问题。延续我之前关于心肌缺血再灌注损伤的基础科学研究然而，距离我上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高级的额外研究培训分子生物学技术和重点职业发展，以过渡到独立额外的研究和职业培训将是非常宝贵的，可以让我回答相关问题。我无法以其他方式研究的问题，在该奖项的支持下，这项工作将提供一个基础。建立麻醉学领域的教师、临床医生和基础科学家的职业生涯。培训环境：斯坦福大学拥有世界一流的杰出职业发展环境和斯坦福大学致力于我作为一名临床医生的发展。科学家，从我提议的医学院成员培训中可以看出，心血管研究所、麻醉科、化学与系统生物学系、我校导师（Daria Mochly-Rosen 博士）、共同导师（Rona Giffard 博士和 David Yeomans 博士）及其实验室我组建了一支具有多学科研究专业知识和转化技能的顾问团队。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职业发展的关键要素包括增强我对蛋白质的了解。我还将获得生物化学、蛋白质-蛋白质相互作用和疼痛信号传导的分子机制。基于细胞的技术和小分子药物开发和设计的额外培训。研究：辣椒通过复合辣椒素产生辣味，进而释放辣椒素内啡肽（我们喜欢辛辣食物的可能原因）激活辣椒素敏感通道，被称为瞬时感受器电位香草酸 1 (TRPV1)，可能不仅仅发出疼痛和随后的信号 TRPV1 可能会激活信号通路，从而减少心脏缺氧造成的损伤。（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。 TRPV1 激活产生的疼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，也会降低糖尿病患者的 TRPV1 表达。心脏病发作时是无声的或无痛的，没有疼痛（TRPV1 激活），是否没有器官的恢复。保护？研究疼痛和保护之间的联系也很重要，因为通过药物减轻疼痛阻断 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。我将通过研究 TRPV1 是否糖基化来确定分子基础（目的） 1) 其次，蛋白激酶 C epsilon (PKC�) 磷酸化 (Aim2)，减少心脏细胞损伤。检查手术室常用药物、阿片类药物和挥发性麻醉剂是否需要 TRPV1 可以减少缺血再灌注损伤（目标 3）。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这些研究将共同确定 TRPV1 敏感性（目标 4）。连接以及阿片类药物和挥发性麻醉剂如何通过 TRPV1 激活启动途径，从而减少心脏病发作受伤。