Identification of Mechanisms by which Insulin Receptor Substrates (IRS) Regulate Cardiomyocyte Metabolism and Survival

胰岛素受体底物 (IRS) 调节心肌细胞代谢和存活的机制的鉴定

• 批准号: 233893572
• 负责人: Dr. Christian Riehle
• 金额: --
• 依托单位: Klinik für Kardiologie und Angiologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233893572?language=en
• 关键词: Identification; Mechanisms; Insulin; Receptor; Substrates

Clinical trials of tight metabolic control in subjects with type 2 diabetes, which involve intensive insulin therapy increased mortality and the number of major cardiovascular events. We have previously shown in a model of pressure overload that hyperinsulinemia per se activates the insulin signaling cascade in the heart and thereby accelerates cell death and heart failure. Insulin and IGF-1 signaling is mediated by insulin receptor substrates (IRS) 1 and 2. Our preliminary studies identified an IRS-isoform specific contribution to cardiac metabolism and growth. In the presence of pressure overload, IRS1-deletion had beneficial effects whereas absence of IRS2 was detrimental. The underlying mechanisms will to be elucidated in this proposal. Furthermore, while mice with cardiomyocyte-specific deletion of either IRS1 or IRS2 had normal survival, knockdown of both IRS isoforms resulted in increased mortality due to heart failure. Similarly, mice with a combined cardiomyocyte-specific deletion of both insulin (IR) and IGF-1 receptors died from heart failure. In addition to IR and IGF-1 receptors, IRS proteins are linked to cytokine receptors and integrins. Therefore, we propose to investigate IR/IGF-1 receptor dependent and independent mechanisms that contribute to heart failure in IRS1/2-deficient hearts. Together, these studies will provide new insight into the IRS isoform-specific modulation of insulin signaling under conditions of pressure overload and dissect the upstream signals that are transduced by IRS1 and IRS2 in cardiomyocytes.

在2型糖尿病受试者中进行严格代谢控制的临床试验，其中包括强化胰岛素治疗，增加了死亡率和主要心血管事件的数量。我们先前已经在压力超负荷模型中表明，高胰岛素血症本身激活心脏中的胰岛素信号级联，从而加速细胞死亡和心力衰竭。胰岛素和IGF-1信号由胰岛素受体底物（IRS）1和2介导。我们的初步研究确定了IRS-亚型对心脏代谢和生长的特异性贡献。在压力超负荷的存在下，IRS 1缺失具有有益的效果，而IRS 2缺失则是有害的。本提案将阐明基本机制。此外，虽然IRS 1或IRS 2心肌细胞特异性缺失的小鼠具有正常的存活率，但两种IRS亚型的敲低导致心力衰竭导致的死亡率增加。类似地，胰岛素（IR）和IGF-1受体联合心肌细胞特异性缺失的小鼠死于心力衰竭。除了IR和IGF-1受体外，IRS蛋白还与细胞因子受体和整合素连接。因此，我们建议调查IR/IGF-1受体依赖性和非依赖性的机制，有助于在IRS 1/2缺陷的心脏心力衰竭。总之，这些研究将提供新的见解IRS异构体特异性调节胰岛素信号的条件下的压力超负荷和解剖的上游信号转导的IRS 1和IRS 2在心肌细胞。

项目成果

Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

• DOI: 10.1128/mcb.01109-14
• 发表时间: 2014-12
• 期刊: Molecular and Cellular Biology
• 影响因子: 5.3
• 作者: A. Wende;Brian T. O’Neill;H. Bugger;C. Riehle;Joseph Tuinei;J. Buchanan;Kensuke Tsushima;Li Wang-

Insulin regulation of myocardial autophagy.

• DOI: 10.1253/circj.cj-14-1080
• 发表时间: 2014
• 期刊: Circulation journal : official journal of the Japanese Circulation Society
• 作者: Riehle C;Abel ED
• 通讯作者: Abel ED

Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training

胰岛素受体底物对于心脏对运动训练的生物能和肥厚反应至关重要

• DOI: 10.1128/mcb.00426-14
• 发表时间: 2014
• 期刊: Molecular and Cellular Biology
• 影响因子: 5.3
• 作者: Riehle C;Wende AR;Oliveira KJ;Pereira RO;Jaishy BP;Bevins J;Valdez S;Kim BJ;Moreira AB;Weatherford ET;Manivel R;Rawlings TA;Rech M;White MF;Abel ED
• 通讯作者: Abel ED