MAP Kinase and AKT Signaling in Congestive Heart Failure

描述（由申请方提供）：心脏肥大和充血性心力衰竭是人类常见疾病，可能是Akt/蛋白激酶B家族异常信号通路激活的结果。该提案的主要目的是研究单个Akt家族成员在心肌细胞生长和代谢中的作用。虽然Akt 1和Akt 2是高度同源的，并在心肌细胞中以接近相等的量表达，我们假设，Akt 1选择性地调节生理性肌细胞生长和Akt 2选择性地调节肌细胞葡萄糖代谢。初步数据表明，Akt 1，而不是Akt 2，可能需要的生理性肥大的发展，在响应胰岛素样生长因子1（IGF-1）刺激培养的心肌细胞或响应生长因子-IGF-1输注小鼠。此外，最初的实验表明，Akt 1是不需要压力超负荷诱导的心肌肥大，Akt 2，而不是Akt 1，需要胰岛素刺激的葡萄糖摄取培养的心肌细胞。在本研究中，将对Akt 1、Akt 2和Akt 3在培养的新生大鼠和成年小鼠心肌细胞的生长和存活中的相对功能进行评价。其次，研究Akt 1和Akt 2在体内心脏的生长和收缩功能中的作用。目前在我们的小鼠群体中可获得的akt T +/-、akt 1 +/-、aktz +/-、aW 2 +/-和野生型小鼠将通过横向主动脉收缩进行压力超负荷和游泳运动训练。第三，Akt家族成员在心脏代谢调节中的作用将通过离体工作心脏分析和aWfA和aM 2-A小鼠的体内微量正电子发射断层扫描研究来检查。最后，将检查Akt 2和过氧化物酶体激活受体α（PPARa）以相互拮抗的方式调节心脏代谢的能力。我们的研究结果将有助于确定参与心肌细胞生长和代谢调节的特定信号机制。

DESCRIPTION (provided by applicant): Cardiac hypertrophy and congestive heart failure are common human ailments that may develop as a consequence of abnormal signaling pathway activation involving the Akt/Protein Kinase B family. The main aim of this proposal is to investigate the role of individual Akt family members in the growth and metabolism of cardiac myocytes. Although Akt1 and Akt2 are highly homologous and are expressed at near-equal amounts in cardiac myocytes, we hypothesize that Akt1 selectively regulates physiologic myocyte growth and that Akt2 selectively regulates myocyte glucose metabolism. Preliminary data shows that Akt1, but not Akt2, may be required for the development of physiologic hypertrophy in response to insulin-like growth factor 1 (IGF-1) stimulation of cultured cardiac myocytes or in response to growth hormone-IGF-1 infusion in mice. Furthermore, initial experiments suggest that Akt1 is not required for pressure overload-induced cardiac hypertrophy, and that Akt2, but not Akt1, is required for insulin-stimulated glucose uptake in cultured cardiac myocytes. In this proposal, the relative functions of Akt1, Akt2, and Akt3 in the growth and survival of cultured neonatal rat and adult murine cardiac myocytes will be evaluated. Second, the role of Akt1 and Akt2 in the growth and contractile function of the in vivo heart will be investigated. aktT'', akt1+/~, aktz'', aW2+/", and wild type mice, currently available in our mouse colony, will be subjected to pressure overload by transverse aortic constriction and to swimming exercise training. Third, the role of Akt family members in the regulation of cardiac metabolism will be examined by ex vivo working heart analysis and by in vivo micro-positron emission tomography studies of aWfA and aM2"A mice. Finally, the ability of Akt2 and Peroxisome-Proliferator Activated Receptor a (PPARa) to regulate cardiac metabolism in a mutually antagonistic manner will be examined. Our findings will help to identify specific signaling mechanisms involved in the regulation of cardiac myocyte growth and metabolism.