Nitric Oxide/cGMP/Endotoxin-Induced Myocardial Dysfunct

描述（由申请人提供）： 该提案描述了一个为期5年的培训计划，用于培养NO/cGMP信号传导和心肌功能障碍领域的独立研究者。 主要研究者是哈佛医学院麻醉系的一名初级教员，具有生理学背景，他现在将获得分子和细胞生物学方面的新知识和技能，以推进他的学术生涯。 该提案将集中于NO/cGMP信号在与全身炎症相关的心肌功能障碍中的作用。 肯尼斯·D布洛赫，医学博士，将指导主要研究者的科学发展。 Bloch博士是NO/cGMP信号传导领域公认的专家，在培养博士后研究员和研究生方面拥有丰富的经验。 为了补充Bloch博士的专业知识，该培训计划邀请Roger J. Hajjar医学博士作为共同发起人，他是心肌细胞和分子生物学以及心脏基因转移方面的专家。 此外，一个由德高望重的医生科学家组成的咨询委员会将提供科学和职业建议。 本实验旨在探讨NOS 2、cGMP和cGMP依赖性蛋白激酶（PKG）在内毒素血症所致心肌功能障碍中的作用。 具体而言，申请方建议评估NOS2是否足以或需要引起内毒素诱导的心肌功能障碍，但不足以引起内毒素诱导的心肌功能障碍。 此外，将检查心肌cGMP浓度增加和PKG活化对全身炎症相关心肌功能障碍的贡献。 将对分离的心肌细胞进行研究，以及使用转基因小鼠和心脏基因转移小鼠进行体内研究。 总之，拟议的研究将阐明NOS2和cGMP依赖性信号传导在与全身炎症相关的心肌功能障碍发病机制中的作用。 该奖项将允许申请人利用马萨诸塞州总医院心血管研究中心的优秀研究培训环境，获得细胞和分子生物学方面的新知识和技能。 此外，一个精心构建的培训计划已经制定，将允许一个独立的研究事业的成功发展，检查与全身炎症相关的心肌功能障碍的基本机制。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an independent investigator in the area of NO/cGMP signaling and myocardial dysfunction. The principal investigator is a junior member of the faculty in the Department of Anesthesia at the Harvard Medical School with a background in physiology, who now will acquire new knowledge and skills in molecular and cellular biology to advance his academic career. This proposal will focus on the role of NO/cGMP signaling in myocardial dysfunction associated with systemic inflammation. Kenneth D. Bloch, MD, will mentor the principal investigator's scientific development. Dr. Bloch is a recognized expert in the field of NO/cGMP signaling and has extensive experience in training postdoctoral fellows and graduate students. To complement Dr. Bloch's expertise, the training program enlists the expertise of Roger J. Hajjar, MD, as a co-sponsor, who is an expert in myocardial cellular and molecular biology, as well as cardiac gene transfer. In addition, an advisory committee of highly respected physician scientists will provide scientific and career advice. The proposed experiments will examine the role of NOS2, cGMP and cGMP-dependent protein kinase (PKG) in the myocardial dysfunction associated with endotoxemia. Specifically, the applicant proposes to assess whether NOS2 is sufficient or required, but not sufficient, to cause endotoxin-induced myocardial dysfunction. In addition, the contribution of increased myocardial cGMP concentrations and PKG activation to the myocardial dysfunction associated with systemic inflammation will be examined. Studies will be performed on isolated cardiomyocytes, as well as in vivo using transgenic mice and mice subjected to cardiac gene transfer. Together, the proposed studies will illuminate the role of NOS2 and cGMP-dependent signaling in the pathogenesis of myocardial dysfunction associated with systemic inflammation. This award will permit the applicant to take advantage of the outstanding research training environment of the Cardiovascular Research Center of the Massachusetts General Hospital for the acquisition of new knowledge and skills in cell and molecular biology. In addition, a carefully constructed training program has been developed that will permit successful development of an independent research career examining the basic mechanisms of myocardial dysfunction associated with systemic inflammation.