MAP Kinase and AKT Signaling in Congestive Heart Failure

充血性心力衰竭中的 MAP 激酶和 AKT 信号转导

• 批准号: 7078575
• 负责人: ANTHONY JUSTIN MUSLIN
• 金额: $ 33.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078575
• 关键词: biological signal transduction; cardiac myocytes; cell growth regulation; congestive heart failure; enzyme activity; glucose metabolism; heart enlargement; insulin sensitivity /resistance; laboratory mouse; mitogen activated protein kinase; peroxisome proliferator activated receptor; protein structure function; serine threonine protein kinase

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.

描述（由申请人提供）：心脏肥大和充血性心力衰竭是常见的人类疾病，由于涉及Akt/蛋白质激酶B家族的异常信号通路激活而可能发展。该提案的主要目的是调查个别AKT家族成员在心肌细胞的生长和代谢中的作用。尽管AKT1和AKT2高度同源，并且在心肌细胞中以接近等量的量表达，但我们假设AKT1选择性调节生理肌细胞的生长，并且AKT2选择性调节心肌细胞葡萄糖代谢。初步数据表明，由于胰岛素样生长因子1（IGF-1）刺激培养的心肌细胞或对小鼠生长激素-IGF-1的响应，可能需要AKT1而不是AKT2来发育生理肥大。此外，初始实验表明，压力超负荷引起的心脏肥大并不需要AKT1，并且在培养的心肌细胞中胰岛素刺激的葡萄糖摄取需要AKT2而不是AKT1。在此提案中，将评估AKT1，AKT2和AKT3在培养的新生大鼠和成年鼠心肌细胞的生长和存活中的相对功能。其次，将研究AKT1和AKT2在体内心脏的生长和收缩功能中的作用。 aktt''，akt1+/〜，aktz''，aw2+/“和目前在我们的鼠标群体中可用的野生型老鼠将受到横向主动脉汇总和游泳运动训练的压力超负荷。 AWFA和AM2“一只老鼠。最后，将检查Akt2和过氧化物酶体增生剂活化受体A（PPARA）以相互拮抗的方式调节心脏代谢的能力。我们的发现将有助于确定与心肌细胞生长和代谢有关的特定信号传导机制。