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

• 批准号: 8296613
• 负责人: Eric Richard Gross
• 金额: $ 13.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296613
• 关键词: Accident and Emergency department; Acute myocardial infarction; 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; Commit; Coronary Artery Bypass; Development; Diabetes Mellitus; 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; 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; Rodent; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Silent Myocardial Infarction; Stimulus; Systems Biology; Taste Perception; Techniques; Therapeutic; Time; Tissues; Training; Translational Research; 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; pleasure; prevent; protein kinase C epsilon; protein protein interaction; receptor; skills; small molecule; teacher

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.

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酸通道 (TRPV1) 在缺血再灌注损伤心肌挽救中的作用。作为一名临床麻醉师，我觉得我拥有在基础科学实验室研究这个具体且相关的临床问题的独特技能。我目前的研究方向是我之前有关心肌缺血再灌注损伤的基础科学研究的逻辑延续，并且与我的临床训练相得益彰。然而，距离我上一次配体诱导心脏保护方面的强化基础科学培训已经过去了 5 年，所以我的近期目标是获得先进分子生物学技术的额外研究培训和重点职业发展，以便过渡为独立研究者。额外的研究和职业培训将是无价的，让我能够回答我无法通过其他方式研究的相关问题。这项工作在该奖项的支持下，将为建立麻醉学教师、临床医生和基础科学家的职业生涯奠定基础。培训环境：斯坦福大学拥有世界一流的职业发展环境以及开展和学习新颖、前沿研究的环境。斯坦福大学致力于我作为一名临床科学家的发展，从我提议的医学院、心血管研究所、麻醉学系、化学和系统生物学系、我的导师（Daria Mochly 博士）的成员那里进行的培训就可以看出这一点。 Rosen）、共同导师（Rona Giffard 博士和 David Yeomans 博士）及其实验室成员。我组建了一支顾问团队，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拥有多学科研究专业知识和技能。研究职业发展的关键要素包括增强我对蛋白质生物化学、蛋白质-蛋白质相互作用和疼痛信号传导分子机制的了解。我还将获得基于细胞的技术以及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，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 (TRPV1)）的激活可能不仅仅发出疼痛和随后的愉悦信号。 TRPV1 可能会激活信号通路，从而减少心脏病发作期间心脏缺氧（缺血）造成的损伤。这可能表明胸痛（心绞痛）实际上是预防心脏病发作损伤的自然途径。 TRPV1 激活产生的疼痛感是否与预防心脏病发作的途径有关？糖尿病会降低 TRPV1 的表达，从而增加心脏病发作的心血管风险。糖尿病患者也会出现无声或无痛的心脏病发作。没有疼痛（TRPV1激活），是否就没有获得器官保护？疼痛和保护之间的联系也很重要，因为通过阻断 TRPV1 通道来减轻疼痛的药物正在进行临床试验。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（目标 1）和蛋白激酶 C epsilon（PKC5）磷酸化（目标 2）是否减少心脏细胞损伤来确定分子基础。然后我将检查手术室中常用的阿片类药物和挥发性麻醉剂是否需要 TRPV1 来减少缺血再灌注损伤（目标 3）。我还将确定在糖尿病中，是否可以通过提高 TRPV1 敏感性来逆转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（目标 4）。这些研究将共同​​确定胸痛和心脏病发作损伤之间的关系，以及阿片类药物和挥发性麻醉剂如何通过 TRPV1 激活启动一条途径，从而减少心脏病发作损伤。