ADENOVIRAL GENE TRANSFER IN MYOCARDIAL INJURY

描述 （改编自申请人的摘要）本指导的中心目的 临床科学家发展奖是准备申请人 作为心脏麻醉学的独立研究者。 的 申请人建议获得分子生物学方面的额外技能， 体细胞基因转移在一个项目的背景下，建立在他的 心肌缺血再灌注损伤的研究经验 vivo. 心肌缺血-再灌注损伤已被确定在许多 临床上重要的疾病，包括急性心肌梗死和 心脏手术 所选项目的目标是了解 一氧化氮（NO）供体在 心肌缺血再灌注损伤（IR）。 申请人先前已经证明内源性NO释放减少了 体内心肌梗死。 然而，系统性NO供体具有复杂的 可能调节许多重要因素的影响， 这些包括循环血液元素（白细胞，血小板， 红细胞）、脉管系统和心脏本身。 申请人 假设NO供体在IR中的有益作用主要来自于 从它们对循环血液元素的影响。 为了验证这个假设， 他们将1）检查NO对心肌细胞存活的直接影响， 采用离体缺血再灌注模型，2）评价吸入 NO气体（专门影响肺循环和肺循环） 循环血液元素）在心脏IR的大鼠模型中，和3）检查 同一大鼠心肌局部一氧化氮合酶（NOS）过度表达的影响 模型，主要影响心脏，在较小程度上， 血液元素在心脏中的循环 通过这种方式， 他们希望确定NO调节局部 （心脏）与全身（循环血液元素）途径 IR衰减。 了解这些途径在心脏IR中的作用， 调节这些途径的方法，可以提供新的治疗方法， 管理重要临床状况的方法， 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.