THE NADH SHUTTLES AND METABOLIC ADAPTATION OF THE HEART

NADH 穿梭和心脏的代谢适应

• 批准号: 6638171
• 负责人: THOMAS D SCHOLZ
• 金额: $ 9.85万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638171
• 关键词: aspartate; biological transport; blood pressure; blood volume; colorimetry; electron transport; enzyme activity; fluorescent dye /probe; gene expression; heart metabolism; laboratory rat; malates; messenger RNA; microarray technology; mitochondria; molecular cloning; nicotinamide adenine dinucleotide; northern blottings; nuclear magnetic resonance spectroscopy; nucleic acid probes; polymerase chain reaction; tissue /cell culture; transcription factor; transport proteins; ventricular hypertrophy; western blottings

Myocardial hypertrophy is an adaptive response to a pressure or volume load. However, patients with ventricular hypertrophy are at increased risk for congestive heart failure, sudden death, and myocardial infarction. The metabolic response of cardiac myocytes to an increased load is known to include activation of several fetal pathways that allow the heart to more efficiently utilize glucose and enhance adenosine triphosphate (ATP) production. We have shown that fetal and neonatal myocardium optimizes ATP production from glucose oxidation through activation of the malate/aspartate (mar/asp) and a-glycerophosphate (a-GP) shuttles. The molecular basis of these and other metabolic adaptations in hypertrophied myocardium are just beginning to be explored. The specific aims of this proposal are to determine if the mal/asp and a- GP shuttles are up-regulated in hypertrophied myocardium, sequence and characterize the aspartate/glutamate carrier (AGC), identify the role of the AGC in regulating mal/asp shuttle flux, and broadly explore molecular regulation of metabolism in hypertrophied myocardium using cDNA microarray techniques. These studies will continue the research career development along a path I have been following for the last decade or more. My commitment to research preceded my postgraduate education and continued through my pediatric cardiology fellowship and postdoctoral training at the NIH. I have been an independent investigator at the University of Iowa for the past six years focusing on studies of the metabolic adaptation of the heart in response to disease and normal development. The research environment at the University of Iowa nurtures young scientists by providing excellent facilities and encouraging collaborations among investigators. It is through collaboration with other investigators that I have learned techniques to expand the questions that can be answered and that has allowed my research career to develop. Unfortunately, focused research time continues to decline as clinical demands increase. Receiving the Independent Scientist Award (K02) would remove most of these clinical duties and allow more concentrated time directed at studying the metabolic development of the heart. This will aid in my long-term goals of increased understanding of the metabolic development of the heart and serving as a role model and guide for clinician-scientists in training.

心肌肥大是对压力或体积负荷的自适应反应。然而，心室肥大患者患有充血性心力衰竭，猝死和心肌梗塞的风险增加。心脏肌细胞对增加负荷的代谢反应包括激活多种胎儿途径，这些胎儿途径使心脏更有效地利用葡萄糖并增强了三磷酸腺苷（ATP）的产生。我们已经表明，胎儿和新生儿心肌通过激活苹果酸/天冬氨酸（MAR/ASP）和A-甘油磷酸盐（A-GP）穿梭来优化从葡萄糖氧化的ATP产生。这些肥厚心肌中这些和其他代谢适应的分子基础刚刚开始探索。该提案的具体目的是确定在肥厚的心肌，序列和表征天冬氨酸/谷氨酸载体（AGC）中，MAL/ASP和A-GP穿梭是否在上调，确定AGC在调节MAL/ASP中的作用穿梭通量，并通过cDNA微阵列技术广泛探索肥厚心肌中代谢的分子调节。这些研究将沿着我过去十年或更长时间以来一直遵循的一条研究职业发展。我对研究的承诺是在我的研究生教育之前，并继续通过NIH的儿科心脏病学研究金和博士后培训。在过去的六年中，我一直是爱荷华大学的独立研究者，重点是研究心脏代谢适应性，以应对疾病和正常发育。爱荷华大学的研究环境通过提供出色的设施并鼓励研究人员合作来培养年轻科学家。正是通过与其他研究人员的合作，我学习了技术来扩大可以回答的问题，并使我的研究职业发展得以发展。不幸的是，随着临床需求的增加，重点的研究时间继续下降。获得独立科学家奖（K02）将删除大多数此类临床职责，并允许更集中的时间研究心脏的代谢发展。这将有助于我长期对心脏代谢发展的了解，并成为培训中临床医生科学家的榜样和指南。