Calpain and Calpastatin Regulation of Reperfusion Injury

钙蛋白酶和钙蛋白酶抑制素对再灌注损伤的调节

• 批准号: 7055340
• 负责人: JEFFREY Martin PEARL
• 金额: $ 32.74万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055340
• 关键词: calpain; cardiovascular disorder therapy; cellular pathology; congenital heart disorder; cytoprotection; gel mobility shift assay; heart /lung bypass; infant animal; laboratory rat; myocardial ischemia /hypoxia; nonhuman therapy evaluation; nuclear factor kappa beta; postoperative complications; protease inhibitor; reperfusion; swine; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Congenital heart disease is the number 1 cause of death from birth defects in the first year of life. Although corrective or palliative surgery for most congenital heart defects can be undertaken in infancy, repair is still associated with mortality and morbidity exceeding that of most pediatric surgical procedures. Cardiopulmonary bypass and myocardial ischemia is typically required for repair and can result in myocardial dysfunction that is temporary, such as myocardial stunning, or permanent, such as occurs with apoptosis. Myocardial protective strategies for infants and children are limited 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. Calpain activity is associated with interruption of calcium-regulated contraction, degradation of contractile proteins, and enhanced cell death. The long-term goal of this proposal is to define mechanisms of myocardial dysfunction after ischemia and reperfusion in children. The immediate goal is to identify pathways that 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 role of nuclear factor-kappaB regulation by calpain and calpastatin in myocardial dysfunction associated with reperfusion in an immature animal model, 2) define the role of calpain in mediating cardiac apoptosis associated with reperfusion of ischemic myocardium, and 3) determine regulatory mechanisms of calpastatin activity after reperfusion. A piglet model of cardiopulmonary bypass and circulatory arrest and in vitro culture of neonatal cardiomyocytes examine the roles of calpain and calpastatin in reperfusion injury of the immature cardiopulmonary system. Determining calpain and calpastatin regulation of these pathways identifies therapeutic targets to reduce postoperative myocardial dysfunction in pediatric patients.

描述（由申请人提供）：先天性心脏病是第一年出生缺陷死亡的头号原因。尽管大多数先天性心脏缺陷的矫正或姑息手术可以在婴儿期进行，但修复术的死亡率和发病率仍然超过大多数儿科外科手术。心脏搭桥术和心肌缺血通常是修复所需的，并且可能导致暂时性的心肌功能障碍，如心肌顿抑，或永久性的心肌功能障碍，如细胞凋亡。婴儿和儿童的心肌保护策略是有限的，往往只是成人治疗的外推。缺血心脏的再灌注刺激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收缩的中断、收缩蛋白的降解和增强的细胞死亡有关。这项建议的长期目标是确定儿童缺血和再灌注后心肌功能障碍的机制。近期目标是确定促进干预措施发展的途径，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和钙蛋白酶抑制剂对核因子-κ B的调节在与再灌注相关的心肌功能障碍中的作用，2）确定钙蛋白酶在介导与缺血心肌再灌注相关的心脏细胞凋亡中的作用，3）确定再灌注后钙蛋白酶抑制剂活性的调节机制。体外循环和停循环的仔猪模型和新生心肌细胞的体外培养研究钙蛋白酶和钙蛋白酶抑制蛋白在未成熟心肺系统再灌注损伤中的作用。确定钙蛋白酶和钙蛋白酶抑制蛋白调节这些途径确定治疗目标，以减少儿科患者术后心肌功能障碍。