GENETIC MODEL OF MYOCARDIAL STUNNING IN IMMATURE HEART

未成熟心脏心肌顿抑的遗传模型

• 批准号: 6208201
• 负责人: DAVID G SOERGEL
• 金额: $ 4.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6208201
• 关键词: gene expression; genetic models; genetically modified animals; heart; heart contraction; heart ventricle; immature animal; inbreeding; laboratory mouse; model design /development; muscle function; myocardial ischemia /hypoxia; myocardium; newborn animals; polymerase chain reaction; protein isoforms; reperfusion; southern blotting; troponin

Myocardial stunning occurs when the heart is exposed to transient ischemia followed by reperfusion. Stunning results in reversible systolic and diastolic dysfunction without histological evidence of myocardial necrosis. Pediatric patients with congenital heart disease are often exposed to transient ischemia during operative repair of their cardiac defects and experience resultant post-operative ischemia during operative repair during operative repair of their cardiac defects and experience resultant post-operative myocardial dysfunction. Proteolytic truncation of the carboxy-terminus of troponin I is linked to the stunned phenotype and recent transgenic work has established that expression of truncated troponin I is sufficient to reproduce the pathophysiology of myocardial stunning. Since neonatal heart expresses the slow skeletal isoform of troponin I for the first several months of life, the contribution of this isoform to stunning is relevant to the care of these children in the peri- operative period. To this end, we propose to elucidate how modification of slow skeletal troponin contributes to stunning using transgenesis with assessment of cardiac muscle function in isolated trabeculae and intact heart. This work should a more complete understanding of the impact of stunning in immature heart and potentially suggest rationale and pediatric-specific therapies for post-ischemic dysfunction.

当心脏遭受短暂缺血并随后再灌注时，就会发生心肌顿抑。令人震惊的结果是可逆的收缩和舒张功能障碍，而没有心肌坏死的组织学证据。患有先天性心脏病的儿科患者在其心脏缺陷的手术修复过程中常常会遭受短暂性缺血，并在其心脏缺陷的手术修复过程中经历由此产生的术后缺血，并经历由此产生的术后心肌功能障碍。肌钙蛋白 I 羧基末端的蛋白水解截短与顿抑表型有关，最近的转基因工作已证实截短肌钙蛋白 I 的表达足以重现心肌顿抑的病理生理学。由于新生儿心脏在生命的最初几个月表达慢速骨骼肌钙蛋白 I 亚型，因此该亚型对致昏的贡献与这些儿童在围手术期的护理有关。为此，我们建议通过评估离体小梁和完整心脏中的心肌功能来阐明慢骨骼肌钙蛋白的修饰如何有助于使用转基因进行击晕。这项工作应该更全面地了解击晕对未成熟心脏的影响，并可能为缺血后功能障碍提出基本原理和儿科特异性疗法。