PGC-1: REGULATOR OF MITOCHONDRIAL METABOLISM IN HEART

成年哺乳动物心脏利用脂肪酸作为其主要能量来源。在肥大中，心脏从脂肪酸氧化（FAO）转换为葡萄糖代谢以产生能量。过氧化物酶体增殖物激活受体α（PPARalpha）调节编码关键FAO酶的基因的表达。FFARalpha是一种核受体转录因子，与共激活蛋白一起激活转录。最近鉴定的共激活剂，PPARgamma共激活剂-1（PGC-1），是与PPARalpha合作调节FAO酶基因的候选者。这两种蛋白质在心肌肥大过程中下调，暗示了PPARalpha/PGC-1信号在肥大基因程序中的作用。PGC-1还显示通过独立于其与PPARalpha的功能的机制调节参与线粒体生物发生的基因。具体目的是1）表征PPARalpha及其共激活剂PGC-1在控制心脏线粒体能量转导途径中的作用，2）共激活剂PGC-1在控制心脏线粒体能量转导途径中的作用，3）绘制PGC-1分子内与显性抑制突变体的发展相关的功能结构域，和3）确定PPARalpha/PGC-1信号传导是否在心肌细胞肥大程序中起主要作用。长期目标包括开发基因工程动物，以研究PGC-1在体内调节心脏代谢中的作用。

The adult mammalian heart utilizes fatty acids as its predominant energy source. In hypertrophy, the heart switches from fatty acid oxidation (FAO) to glucose metabolism for energy generation. The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates expression of genes encoding key FAO enzymes, FFARalpha is a nuclear receptor transcription factor that functions with co-activator proteins to activate transcription. The recently identified co-activator, PPAR gamma co- activator-1 (PGC-1), is a candidate for cooperating with PPARalpha to regulate FAO enzyme genes. Both proteins are down-regulated during cardiac hypertrophy, implicating a role for PPARalpha/PGC-1 signaling in the hypertrophy gene program. PGC-1 has also been shown to regulate genes involved in mitochondrial biogenesis by a mechanism independent of its function with PPARalpha. The specific aims are to 1) characterize the role of PPARalpha and its, co-activator, PGC-1, in the control of cardiac mitochondrial energy transduction pathways, 2) co-activator, PGC-1, in the control of cardiac mitochondrial energy transduction pathways, 3) map functional domains within the PGC-1 molecular relevant to the development of dominant inhibitory mutants, and 3) determine whether PPARalpha/PGC-1 signaling plays a primary role in the cardiac myocyte hypertrophy program. Long-term goals involve development of genetically engineered animals to investigate the roles of PGC-1 in regulating cardiac metabolism in vivo.