ADENOVIRAL GENE TRANSFER IN MYOCARDIAL INJURY

描述 (改编自申请者的摘要)这项指导的中心目的 临床科学家发展奖是为申请者准备 作为心脏麻醉学的独立研究员的职业生涯。这个 申请者建议获得额外的分子生物学技能和 在一个建立在他的基础上的项目的背景下的体细胞基因转移 大鼠心肌缺血再灌注损伤的研究进展 活着。心肌缺血-再灌注损伤已被发现在许多 临床上重要的疾病包括急性心肌梗死和 心脏手术。选定项目的目标是了解 一氧化氮(NO)供体的有益作用机制 心肌缺血再灌注损伤(IR)。 申请人先前已经证明内源性NO释放减少 活体心肌梗死。然而，系统性的非捐赠者有复杂的 潜在地调节发展中的许多重要元素的影响 投资者关系。这些包括循环血液元素(白细胞、血小板和 红细胞)、血管系统和心脏本身。申请者 假设非供体在IR中的有益影响主要源于 通过它们对血液循环元素的影响。为了检验这一假设， 他们将1)研究一氧化氮对心脏细胞存活的直接影响。 体外脑缺血再灌流模型，2)评价雾化吸入的作用 没有气体(这只会影响肺循环和 循环血液成分)，以及3)检查 大鼠心脏局部一氧化氮合酶(NOS)过度表达的影响 模型，主要影响心脏，在较小程度上， 血液循环中的元素在心脏中流动。就这样， 他们希望定义不调制局部的相对重要性 (心脏)与全身(循环血液元素)途径 红外衰减。 了解这些通路在心脏IR发生和发展中的作用 调节这些通路的方法可能提供新的治疗方法 重要临床情况的管理方法，如 心肌梗死和心脏手术。

DESCRIPTION (Adapted from applicant's abstract) The central purpose of this Mentored Clinical Scientist Development Award is to prepare the applicant for a career as an independent investigator in cardiac anesthesiology. The applicant proposes to acquire additional skills in molecular biology and somatic gene transfer in the context of a project that builds upon his previous experience in studying myocardial ischemia-reperfusion injury in vivo. Myocardial ischemia-reperfusion injury has been identified in many clinically important conditions including acute myocardial infarction and cardiac surgery. The goal of the selected project is to understand the mechanisms underlying the beneficial effects of nitric oxide (NO) donors in cardiac ischemia reperfusion injury (IR). The applicant has previously demonstrated that endogenous NO release reduces myocardial infarction in vivo. However, systemic NO-donors have complex effects that potentially modulate many elements important in the development of IR. These include circulating blood elements (leukocytes, platelets, and erythrocytes), the vasculature, and the heart itself. The applicants hypothesize that the beneficial effects of NO-donors in IR derive primarily from their effect on circulating blood elements. To test this hypothesis, they will 1) examine the direct effects of NO on cardiocyte survival in an in vitro model of ischemia-reperfusion, 2) evaluate the effects of inhaled NO gas (which exclusively affects the pulmonary circulation and the circulating blood elements) in a rat model of cardiac IR, and 3) examine the effects of local cardiac overexpression of NO synthase (NOS) in the same rat model, to affect the heart primarily and, to a lesser extent, the circulating blood elements as they traffic through the heart. In this way, they hope to define the relative importance of NO modulation of local (cardiac) versus systemic (circulating blood elements) pathways in the attenuation of IR. Understanding the role of these pathways in cardiac IR and developing approaches to modulation of these pathways, may provide novel therapeutic approaches for the management of important clinical conditions such as myocardial infarction and cardiac surgery.