Nitric Oxide/cGMP/Endotoxin-Induced Myocardial Dysfunct

描述(由申请人提供)： 本提案描述了一项为期5年的培训计划，旨在培养一名在NO/cGMP信号和心肌功能障碍领域的独立调查员。首席研究员是哈佛医学院麻醉系的初级教员，具有生理学背景，现在将获得分子和细胞生物学的新知识和技能，以推进他的学术生涯。 这项建议将集中在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首席研究员的科学发展。Bloch博士是NO/cGMP信号领域公认的专家，在培训博士后研究员和研究生方面拥有丰富的经验。为了补充布洛赫博士的专业知识，该培训项目邀请了医学博士罗杰·J·哈贾尔的专业知识作为共同发起人，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，一个由备受尊敬的内科科学家组成的咨询委员会将提供科学和职业建议。 拟议的实验将研究NOS2、cGMP和cGMP依赖的蛋白激酶(PKG)在内毒素血症相关的心肌功能障碍中的作用。具体地说，申请人建议评估NOS2是否足以或需要(但不充分)导致内毒素诱导的心肌功能障碍。此外，还将研究心肌cGMP浓度升高和PKG激活对与全身炎症相关的心肌功能障碍的影响。研究将在分离的心肌细胞上进行，以及使用转基因小鼠和接受心脏基因转移的小鼠进行体内研究。总之，拟议的研究将阐明NOS2和cGMP依赖的信号在与全身炎症相关的心肌功能障碍的发病机制中所起的作用。 该奖项将允许申请者利用马萨诸塞州总医院心血管研究中心出色的研究培训环境，获得细胞和分子生物学方面的新知识和技能。此外，还制定了精心设计的培训计划，使其能够成功地开展独立的研究工作，研究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.