ENERGY METABOLISM AS A REGULATOR OF THE MYOCARDIUM

基思考克斯很早就对开发研究心肌疾病的小鼠模型表现出浓厚的兴趣。他的博士学位。培训涉及转基因和基因靶向小鼠模型的生成和操作。我们建议使用代谢性心肌病小鼠模型来研究能量代谢与心肌稳态和基因表达调节之间的相互作用。长链脂肪酸β-氧化是工作心脏中ATP的主要来源，通过使用遗传或药理学方法消除线粒体β-氧化所必需的特定催化酶的活性，长链脂肪酸β-氧化将在代谢途径的沿着精确点处被破坏。长链脂肪酸氧化（FAO）将在两个水平上被破坏：（1）在长链脂肪酸转移到肉毒碱之前，易位到线粒体基质和（2）β-氧化速率调节步骤催化的长链酰基辅酶A脱氢酶（Acadl）和极长链酰基辅酶A脱氢酶（Acadvl）。已经产生了在Acadl和Acadvl中具有无效突变的小鼠。在代谢途径的这些点上破坏FAO将允许在细胞内长链酰基肉毒碱升高或不升高的情况下研究心肌结构/功能、基因表达和细胞信号传导事件，认为长链酰基肉毒碱具有毒性和致炎性。通过靶向这些水平，与破坏β-氧化相关的心肌病的发病机制可以与异常毒性代谢产物的影响一起或分开研究。辛辛那提大学儿童医学中心的分子心血管生物学部门因其在开发和使用小鼠模型以促进对心血管疾病的理解方面的工作而享誉国际。共同发起人Jeffery Molkentin和Jeffrey Robbins积极并成功地领导了使用小鼠模型研究心脏肥大疾病发展和进展的研究项目。

Keith Cox has shown an early and committed interest in developing mouse models to study myocardial disease. His PhD. training involved the generation and manipulation of transgenic and gene targeted mouse models. We propose to investigate the interplay between energy metabolism and the regulation of myocardial homeostasis and gene expression by using mouse models of metabolic cardiomyopathy. Long- chain fatty acid beta-oxidation, the predominant source of ATP in the working heart will be disrupted at precise points along the metabolic pathway by ablating the activity of specific catalytic enzymes essential for mitochondrial beta-oxidation using genetic or pharmacological methods. Long-chain fatty acid oxidation (FAO) will be disrupted at two levels: (1) at long-chain fatty acid transesterification to carnitine prior to translocation into the mitochondrial matrix and (2) the beta-oxidation rate-regulating step catalyzed by long-chain acyl-coenzyme A dehydrogenases (Acadl) and very long-chain acyl-coenzyme A dehydrogenases (Acadvl). Mice with null mutations in Acadl and Acadvl have been generated. Disrupting FAO at these points in the metabolic pathway will allow myocardial structure/function, gene expression, and cell signaling events to be investigated with or without elevations of intracellular long-chain acylcarnitines, considered to be toxic and arrhythmogenic. By targeting these levels, the pathogenesis of cardiomyopathy associated with disrupted beta-oxidation can be studied together or apart from the influence of abnormal, toxic metabolites. The Division of Molecular Cardiovascular Biology at Children's Medical Center of the University of Cincinnati is internationally known for its work in the development and use of mouse models to advance understanding of cardiovascular disease. The co-sponsors, Jeffery Molkentin and Jeffrey Robbins have actively and successfully led research programs using mouse models to study the development and progression of cardiac hypertrophy is disease.