CASPASE INHIBITION OF APOPTOSIS, INFANT CARDIAC SURGERY

描述（来自申请人摘要的逐字）： 先天性心脏病修复的成功结果是发展 心室功能障碍虽然病因无疑是多因素的， 有证据表明，这在很大程度上可能是由于肌细胞丢失， 慢性发绀，长期暴露于异常血流动力学负荷， 心脏手术所需的一次或多次缺血-再灌注发作。 心肌细胞的死亡可以通过坏死或凋亡发生。相比 坏死，凋亡是细胞的有序解体， 由多种基因， 环境和毒性刺激。最近，人类和动物研究表明， 缺氧、缺血-再灌注、异常机械负荷和 炎症可引起显著的心肌细胞凋亡。这种情况发生在 心肌缺血、梗塞、肥大和心力衰竭。的作用 接受心脏手术的婴儿中的细胞凋亡是未知的。基于该 根据我们实验室的信息和初步数据，我们认为， 细胞凋亡在正常和肥大的婴儿中是一个重要的问题， 进行手术缺血-再灌注的心肌。这种肌细胞的损失 将对婴儿心肌特别有害， 由未来的生长和残余的血流动力学异常所施加。 因为在这种情况下触发细胞凋亡的途径是多种多样的，我们有 选择专注于半胱天冬酶的作用。胱天蛋白酶是 细胞凋亡的传播和执行点，并直接负责 用于该方法所需的特定蛋白质的蛋白水解裂解， 发生.目标I中的实验将是第一个定义哪些半胱天冬酶是 表达，激活，以及哪些关键的细胞内蛋白质被切割 在暴露于外科手术的正常和肥大心肌中， 缺血-再灌注，2）量化在此缺血-再灌注中发生的细胞凋亡的量。 3）确定特异性胱天蛋白酶抑制对这些细胞的影响。 事件使用一种新的工作心脏移植模型， 肥大的婴儿心脏，目标二将回答一个关键的问题， 重要性，即抑制半胱天冬酶和细胞凋亡的作用是什么 对长期心肌炎症纤维化和功能恢复的影响这些 实验将是第一个研究有益与有害的作用， 心肌缺血再灌注损伤中细胞凋亡的研究进展总的来说，这些研究 将为治疗靶点和策略提供有价值的新见解， 保护这些患者的心肌功能。结果也可能 适用于缺血、心肌梗死和心脏病患者 失败

DESCRIPTION (Verbatim from Applicant's Abstract): A major limitation to successful outcome of the repair of congenital heart lesions is the development of ventricular dysfunction. While the etiology is undoubtedly multifactorial, evidence suggests that it in large part may be due to myocyte loss resulting from chronic cyanosis, prolonged exposure to abnormal hemodynamic loads, and one or more episodes of ischemia-reperfusion required for cardiac surgery. Death of myocytes can occur by either necrosis or apoptosis. In contrast to necrosis, apoptosis is the orderlv disassemblv of the cell by specific enzymatic pathways that are triggered by a wide variety of genetic, environmental and toxic stimuli. Recently, human and animal studies have shown that hypoxia, ischemia-reperfusion, abnormal mechanical loading, and inflammation can cause significant cardiomyocyte apoptosis. This occurs during myocardial ischemia, infarction, hypertrophy, and heart failure. The role of apoptosis in infants undergoing cardiac surgery is not known. Based upon this information and preliminary data from our laboratory, we believe that myocyte apoptosis is a significant problem in infants with normal and hypertrophied myocardium subjected to surgical ischemia-reperfusion. This loss of myocytes will be particularly injurious to the infant myocardium because of the loads imposed by future growth and residual hemodynamic abnormalities. Because the pathways triggering apoptosis in this setting are multiple, we have chosen to focus on the role of the caspase enzymes. Caspases are the focal point of propagation and execution of apoptosis, and are directly responsible for the proteolytic cleavage of specific proteins required for the process to occur. Experiments in Aim I will be the first to l)define which caspases are expressed, activated, and what key intracellular proteins are thereby cleaved in normal and hypertrophied myocardium exposed to surgical ischemia-repercusion, 2)quantify the amount of apoptosis that occurs in this setting, and 3)determine the effects of specific caspase inhibition on these events. Using a novel working heart transplant model with normal and hypertrophied infant hearts, Aim II will answer a question of critical importance, namely what is the effect of inhibition of caspases and apoptosis on long-term myocardial inflammation, fibrosis, and recovery of function? These experiments will be the first to study the beneficial versus harmful roles of apoptosis in myocardial ischemia-reperfusion injury. Overall, these studies will provide valuable new insights into therapeutic targets and strategies to preserve myocardial function in these patients. The results are also likely to be applicable to patients with ischemia, myocardial infarction, and heart failure.