THYROID REGULATION IN DEVELOPING HEART

心内直视手术后心功能不全经常持续 婴儿和儿童。术后收缩功能衰竭的原因分析 这个年龄段的人往往不清楚，但有时被归因于 术中心肌保护不足。甲状腺激素 调节成人手术后的收缩功能。这 这种现象在未成熟的心脏中尚未被检测到，尽管心脏 功能障碍与有氧运动引起的甲状腺水平下降有关 儿童肺搭桥术。我们假设这些骚乱发生在 甲状腺激素动态平衡破坏线粒体功能 在体内发育的心脏中成熟。在具体问题上的不足 线粒体膜蛋白随后限制了ATP的生产和供应 对于收缩过程来说是必要的。在我们的网站获得的初步数据 实验室表明，甲状腺激素缺乏确实会改变 体内线粒体成熟和呼吸控制。这些 改变同时发生在主要基因表达减少的同时 线粒体膜蛋白，腺嘌呤核苷酸转运体。 我们建议定义与甲状腺调节相关的成熟事件。 线粒体在体内的成熟。随后，我们将确定 这些事件在新生儿模型中的重要性，该模型模拟临床 体外循环、缺血和再灌流。最后是T3 手术期间的补充将作为一种改善模式进行测试 这些线粒体对术后心功能的影响 机械装置。实施了新的磁共振波谱技术 在绵羊体内将成为主要的研究工具，用于 结合代谢和分子生物学技术。这 综合方法此前已被证明在划定 之前未知的与成熟相关的线粒体事件， 缺血和体外循环。具体目标是：1)界定和 甲状腺在成熟心肌呼吸控制中的作用特征 在活体内；b)表征甲状腺对心肌线粒体的影响 利用两种线粒体蛋白质腺嘌呤核苷酸的生物发生 转运子(ANT)和β-F1-ATPase为记者。2 a)确定 TH强烈刺激心肌功能和线粒体呼吸 与循环骤停和搭桥相关的缺血后；b) 确定甲状腺刺激对能量的长期影响 代谢、线粒体生物发生及其与收缩的关系 发育中的心脏在心脏缺血后的功能。

Ventricular dysfunction frequently persists after open heart surgery in infants and children. The cause of postoperative contractile failure in this age group is often unclear, but is sometimes attributed to inadequate intraoperative myocardial protection. Thyroid hormone regulates contractile function postoperatively in adults. This phenomenon has not been examined in the immature heart, though cardiac dysfunction relates to drops in thyroid levels induced by cardio- pulmonary bypass in children. We postulate that these disturbances in thyroid hormone homeostasis disrupt mitochondrial function and maturation in the developing heart in vivo. Deficiencies in specific mitochondrial membrane proteins then limit the ATP production and supply necessary for contractile processes. Preliminary data obtained in our laboratory indicate that thyroid hormone deficiency does alter mitochondrial maturation and respiratory control in vivo. These alterations occur concurrently with decreased expression of a major mitochondrial membrane protein, the adenine nucleotide translocator. We propose defining maturational events related to thyroid regulation of mitochondrial maturation in vivo. Subsequently, we will determine the importance of these events in a neonatal model, which emulates clinical cardiopulmonary bypass, ischemia, and reperfusion. Finally T3 supplementation during surgery will be tested as a mode to improve postoperative cardiac function by effecting these mitochondrial mechanisms. Novel magnetic resonance spectroscopy techniques performed in sheep in vivo will be a principal investigative tool, used in conjunction with metabolic and molecular biology techniques. This integrative approach has previously proved effective in delineating previously unrecognized mitochondrial events related to maturation, ischemia and cardiopulmonary bypass. Specific aims are: 1 a) Define and characterize thyroid effect on maturation myocardial respiratory control in vivo; b) Characterize thyroid effects on cardiac mitochondrial biogenesis using two mitochondrial proteins the adenine nucleotide translocator (ANT) and beta-F1-ATPase as reporters. 2 a) Determine if TH acutely stimulates myocardial function and mitochondrial respiration following ischemia associated with circulatory arrest and bypass; b) Determine longer term effects of thyroid stimulation on energy metabolism, mitochondrial biogenesis and their relation to contractile function following cardiac ischemia in the developing heart.