项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

BALIJEPALLI, RAVI C

项目受资助机构

STANFORD UNIVERSITY

项目编号

5R00HL109212-05

立项年度

2016

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

230381.00美元

学科

Cardiovascular; Diabetes; Heart Disease; Heart Disease - Coronary Heart Disease; Nutrition; Pain Conditions - Chronic; Pain Research;

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

GROSS, ERIC RICHARD

参与机构

NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

项目标书摘要：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.