Alleviation of Reperfusion-Mediated Cardiac Dysfunction

缓解再灌注介导的心脏功能障碍

• 批准号: 6768083
• 负责人: JEFFREY Martin PEARL
• 金额: $ 7.45万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6768083
• 关键词: apoptosis; biological models; calpain; cytoskeletal proteins; immature animal; immunocytochemistry; myocardial ischemia /hypoxia; myocardium disorder; pediatrics; protease inhibitor; reperfusion; swine; transfection

DESCRIPTION (provided by applicant): One child in 150 births suffers from congenital heart disease, which remains a leading cause of infant mortality. As diagnoses and support systems improve, more children are undergoing cardiac surgery to palliate complex congenital defects earlier in life. The increased susceptibility of the immature myocardium to ischemia and the prolonged cardiopulmonary bypass (CPB) period required for repair of congenital defects often result in myocardial dysfunction after pediatric cardiac surgery. Myocardial protective strategies for infants and children are lacking and often are only extrapolations of adult therapies. Reperfusion of ischemic heart stimulates the activity of cysteine proteases called calpains and their endogenous inhibitor, calpastatin, in cardiomyocytes. Calpain activity is associated with interruption of calcium-regulated myocyte contraction, degradation of myocardial contractile proteins, and enhanced cell death. The long-term goal of this application is to define mechanisms contributing to myocardial dysfunction after ischemia and reperfusion in children. The immediate goal is to identify pathways in myocardium that can facilitate development of interventions to reduce postoperative reperfusion injury. The hypothesis is that calpain and calpastatin pathways are critical mediators of reperfusion injury in immature myocardium. The specific aims of this project are: 1) determine the degree to which augmentation of calpastatin expression can reduce myocardial dysfunction associated with ischemia and reperfusion in an immature animal model, 2) define the role of calpastatin in mediating cardiac apoptosis associated with reperfusion injury, and 3) establish mechanisms by which calpain and calpastatin regulate changes in contractile proteins after reperfusion of ischemic myocardium. Adenoviral-mediated gene transfer of calpastatin domains with two distinct functions for mediating calcium influx and inhibiting calpain activity examines the roles of calpain and calpastatin in a clinically relevant piglet model of reperfusion injury. Determining calpain and calpastatin regulation of the cell death cascade and degradation of myocardial contractile proteins, such as troponin I, identifies new therapeutic targets for intervention to reduce postoperative myocardial dysfunction in pediatric patients.

描述（由申请人提供）：每150名新生儿中就有一名患有先天性心脏病，这仍然是婴儿死亡的主要原因。随着诊断和支持系统的改善，更多的儿童正在接受心脏手术，以减轻生命早期的复杂先天性缺陷。未成熟心肌对缺血的敏感性增加以及先天性缺陷修复所需的体外循环（CPB）时间延长通常会导致小儿心脏手术后的心肌功能障碍。婴儿和儿童的心肌保护策略缺乏，往往只是成人治疗的外推。缺血心脏的再灌注刺激心肌细胞中称为钙蛋白酶的半胱氨酸蛋白酶及其内源性抑制剂钙蛋白酶抑制剂的活性。钙蛋白酶活性与钙调节的心肌细胞收缩的中断、心肌收缩蛋白的降解和增强的细胞死亡有关。本申请的长期目标是确定导致儿童缺血和再灌注后心肌功能障碍的机制。目前的目标是确定心肌中的通路，可以促进干预措施的发展，以减少术后再灌注损伤。这一假说认为钙蛋白酶和钙蛋白酶抑制素途径是未成熟心肌再灌注损伤的关键介质。本研究的具体目的是：1）在未成熟动物模型中确定钙蛋白酶抑制蛋白表达增加可以减少与缺血和再灌注相关的心肌功能障碍的程度，2）确定钙蛋白酶抑制蛋白在介导与再灌注损伤相关的心脏细胞凋亡中的作用，3）建立钙蛋白酶和钙蛋白酶抑制蛋白调节缺血心肌再灌注后收缩蛋白变化的机制。腺病毒介导的钙蛋白酶抑制蛋白结构域的基因转移具有介导钙内流和抑制钙蛋白酶活性的两种不同功能，研究了钙蛋白酶和钙蛋白酶抑制蛋白在临床相关的再灌注损伤仔猪模型中的作用。确定钙蛋白酶和钙蛋白酶抑制素调节细胞死亡级联反应和心肌收缩蛋白（如肌钙蛋白I）降解，确定新的干预治疗靶点，以减少儿科患者术后心肌功能障碍。