THYROID REGULATION IN DEVELOPING HEART

心脏直视手术后心室功能障碍经常持续存在， 婴儿和儿童 术后收缩功能衰竭的原因 在这个年龄组往往是不清楚的，但有时归因于 术中心肌保护不足。 甲状腺激素 调节成人术后的收缩功能。 这 这种现象尚未在未成熟的心脏中进行检查，尽管心脏 功能障碍与心血管疾病引起的甲状腺水平下降有关， 小儿肺动脉旁路移植术 我们假设，这些扰动在 甲状腺激素稳态破坏线粒体功能， 在体内发育的心脏中成熟。 具体的防御 线粒体膜蛋白则限制ATP的产生和供应 收缩过程所必需的。 在我们的初步数据中获得的 实验室表明，甲状腺激素缺乏确实会改变 线粒体成熟和呼吸控制。这些 这种改变与一种主要的 线粒体膜蛋白，腺嘌呤核苷酸转运蛋白。 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， 心肺分流术、缺血和再灌注。 最后，T3 手术期间的补充将被测试作为一种模式，以改善 术后心脏功能通过影响这些线粒体 机制等 新的磁共振波谱技术进行 在绵羊体内将是主要的研究工具，用于 结合代谢和分子生物学技术。 这 综合方法以前被证明是有效的， 以前未被认识到的与成熟有关的线粒体事件， 缺血和心肺分流术。 具体目标是：1 a）界定和 表征甲状腺对成熟心肌呼吸控制的影响 体内; B）表征甲状腺对心脏线粒体作用 利用两种线粒体蛋白腺嘌呤核苷酸 转运子（ANT）和β-F1-ATP酶作为报告基因。2 a）确定是否 TH急性刺激心肌功能和线粒体呼吸 在与循环停止和旁路相关的局部缺血之后; B） 确定甲状腺刺激对能量的长期影响 代谢、线粒体生物合成及其与收缩 发育中的心脏在心肌缺血后的功能。

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.