Protection of the Senescent Heart with Metabolic Support

通过代谢支持保护衰老心脏

• 批准号: 6763182
• 负责人: KURT William SAUPE
• 金额: $ 11.94万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763182
• 关键词: adenosine monophosphate; aging; animal old age; bioenergetics; enzyme activity; enzyme induction /repression; enzyme mechanism; free fatty acids; glucose; heart function; heart metabolism; insulin; insulin sensitivity /resistance; intermolecular interaction; isolation perfusion; laboratory rat; lactates; mature animal; messenger RNA; nuclear magnetic resonance spectroscopy; pharmacology; postdoctoral investigator; protein kinase; protein structure function; tissue /cell preparation

DESCRIPTION (from the application): The enzyme 5'AMPK is increasingly regarded as a master controller of cellular metabolism. In the senescent heart, there appear to be changes in this enzyme system, either in the upstream regulation of 5'AMPK, the amount of the enzyme, or the downstream responses to activation of the enzyme. The overall goal of the proposed research is to define on a molecular level how this enzyme is regulated in the heart, how that regulation changes with age, and what role changes in this enzyme with age play in causing the insulin resistance that occurs with aging. The initial step in accomplishing this goal is to determine how the amount of mRNA and protein of this enzyme change with age, and define more completely what regulates 5'AMPK activity. The second step is to determine whether changes in the 5'AMPK system with age contribute to insulin resistance, and whether age-associated insulin resistance can be reversed with chronic pharmacological stimulation of 5'AMPK. This second step will be accomplished using a unique preparation where the following key steps in the 5'AMPK pathway can be measured in isolated hearts: left ventricular contractile function, the concentrations of known and putative allosteric regulators of 5'AMPK, and cardiac uptake of oxygen, glucose, lactate and free fatty acids. The applicant's long-term career goal is to become an independent investigator studying age-associated changes in myocardial metabolism, and their role in heart disease. In the applicant's recent studies it has become apparent that accomplishing this goal will require learning cellular and molecular techniques that can be applied to studying myocardial metabolism during senescence. The techniques in the proposed research are designed to complement the applicant's experience in cardiac energetics/NMR spectroscopy. Through interactions with Dr. Lakatta and the strong biogerontology research community at Boston University School of Medicine (two training grants and a Gerontology Center), the applicant will be instructed in the methodological issues central to the study of biogerontology research.

描述（来自申请）：5'AMPK 酶越来越多地被 被认为是细胞代谢的主控制器。在衰老中 心脏，这个酶系统似乎发生了变化，无论是在 5'AMPK 的上游调节、酶的量或下游 对酶激活的反应。拟议的总体目标 研究的目的是在分子水平上定义这种酶是如何在 心脏，这种调节如何随着年龄而变化，以及其中的作用发生变化 随着年龄的增长，酶会引起胰岛素抵抗，而胰岛素抵抗是随着年龄的增长而发生的。 实现这一目标的第一步是确定如何 这种酶的mRNA和蛋白质随着年龄的增长而变化，并且定义更完整 5'AMPK 活性的调节因素。第二步，判断是否 5'AMPK 系统随年龄的变化会导致胰岛素抵抗，并且 与年龄相关的胰岛素抵抗是否可以通过慢性 5'AMPK 的药理刺激。这第二步就完成了 使用独特的制备方法，其中 5'AMPK 途径中的以下关键步骤 可以在离体心脏中测量：左心室收缩功能、 已知和推定的 5'AMPK 变构调节剂的浓度，以及 心脏吸收氧气、葡萄糖、乳酸和游离脂肪酸。 申请人的长期职业目标是成为一名独立调查员 研究与年龄相关的心肌代谢变化及其在 心脏病。在申请人最近的研究中，很明显的是 实现这一目标需要学习细胞和分子 可用于研究心肌代谢的技术 衰老。拟议研究中的技术旨在补充 申请人在心脏能量学/核磁共振波谱学方面的经验。通过 与拉卡塔博士和强大的生物老年学研究社区的互动 波士顿大学医学院（两项培训补助金和老年学 中心），申请人将在方法问题中心得到指导 生物老年学研究。