ENERGY METABOLISM AS A REGULATOR OF THE MYOCARDIUM

凯斯·考克斯（Keith Cox）很早就对开发小鼠模型来研究心肌疾病表现出了坚定的兴趣。他的博士学位。训练包括转基因和基因靶向小鼠模型的产生和操作。我们拟通过小鼠代谢性心肌病模型研究能量代谢与心肌稳态和基因表达调控之间的相互作用。长链脂肪酸-氧化，工作心脏中ATP的主要来源，将在代谢途径的精确点上被破坏，通过使用遗传或药理学方法消融线粒体-氧化所必需的特定催化酶的活性。长链脂肪酸氧化（FAO）将在两个层面上被破坏：(1)在长链脂肪酸在转位到线粒体基质之前转化为肉碱的过程中；(2)由长链酰基辅酶A脱氢酶（Acadl）和极长链酰基辅酶A脱氢酶（Acadvl）催化的β -氧化速率调节步骤。已经产生了Acadl和Acadl零突变的小鼠。在代谢途径的这些点破坏FAO将允许心肌结构/功能、基因表达和细胞信号事件被研究，无论细胞内长链酰基肉碱是否升高，都被认为是有毒的和致心律失常的。通过靶向这些水平，与β -氧化破坏相关的心肌病的发病机制可以一起研究，也可以不受异常毒性代谢物的影响。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厚疾病的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.