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: 6967075
• 负责人: ANTHONY JUSTIN MUSLIN
• 金额: $ 34.43万
• 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/6967075
• 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，可能是由于涉及 Akt/蛋白激酶 B 家族的信号通路异常激活而导致的。该提案的主要目的是研究 Akt 家族个体成员在心肌细胞生长和代谢中的作用。尽管 Akt1 和 Akt2 高度同源，并且在心肌细胞中表达量接近相同，但我们假设 Akt1 选择性调节生理性心肌细胞生长，而 Akt2 选择性调节心肌细胞葡萄糖代谢。初步数据表明，在胰岛素样生长因子 1 (IGF-1) 对培养的心肌细胞的刺激或对生长激素-IGF-1 输注的反应中，生理性肥大的发生可能需要 Akt1，而不是 Akt2。老鼠。此外，初步实验表明，压力超负荷引起的心脏肥大不需要 Akt1，而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。在本提案中，将评估 Akt1、Akt2 和 Akt3 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。其次，将研究 Akt1 和 Akt2 在体内心脏生长和收缩功能中的作用。 aktT''、akt1+/~、aktz''、aW2+/"以及我们小鼠群体中现有的野生型小鼠，将通过横主动脉缩窄和游泳运动训练来承受压力超负荷。三、Akt的作用将通过 aWfA 和 aM2"A 小鼠的离体工作心脏分析和体内微正电子发射断层扫描研究来检查家庭成员在心脏代谢调节中的作用。最后，将检查 Akt2 和过氧化物酶体增殖物激活受体 a (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调节心肌细胞生长和代谢的特定信号机制。