Signaling mechanisms of cardioprotection and remodeling

描述（由申请人提供）：心肌细胞死亡已在许多临床重要的心脏疾病中被确定，包括心力衰竭、缺血性损伤和梗死后心室重构。急性和慢性表达igf - 1在急性心脏损伤和慢性重构模型中具有心脏保护作用。相反，虽然下游激酶Akt的急性激活也具有心脏保护作用，并被认为介导了IGF-I的许多作用，但我们的初步数据表明，Akt的慢性激活具有与信号分子IRS-1和PI3K的反馈抑制相关的有害影响。这些研究表明，在缺乏PI3K激活的情况下，由于其他关键下游信号的丢失，Akt不足以起到心脏保护作用。当前提案的总体目标是确定和定义由igf - 1激活的akt不依赖的心脏保护机制在急性缺血性损伤和梗死后心室重构中的作用。该建议基于3个假设：1)慢性Akt激活导致IRS-1和PI3K的反馈抑制，从而导致本研究中出现的不良结果；2)不同的、依赖pi3k的信号通路对于完全的心脏保护是必要的；3)常见的信号通路也可以调节梗死后的心室重构。为了验证这些假设，在心肌细胞死亡、缺血性损伤和心室重构模型中，igf - 1的心脏表达以及突变型和野生型下游信号分子将通过体细胞和种系基因转移实现。在Specific Aim 1中，我们将验证IRS-1/PI3K的反馈抑制是慢性Akt激活的有害影响的假设。在特异性目标2中，我们将确定体外和体内igf - 1表达对心肌细胞存活和功能的益处的不依赖于akt的心脏保护机制。在特异性目标3中，我们将验证这些通路也调节梗死后心室重构的假设。在Specific Aim 4中，我们将研究优化的心脏保护效应器的基因转移是否可以减轻梗死后的不良心室重构。了解特定途径在心肌细胞存活中的作用，并通过基因转移学习局部操纵这些途径，可能为梗死后急性缺血性损伤和心室重构的治疗提供新的治疗方法。

DESCRIPTION (provided by applicant): Cardiomyocyte death has been identified in many clinically important cardiac conditions including heart failure, ischemic injury, and ventricular remodeling after infarction. Acute and chronic expression of IGF-I is cardioprotective in models of acute cardiac injury and chronic remodeling. In contrast, while acute activation of the downstream kinase, Akt, is also cardioprotective and thought to mediate many effects of IGF-I, our preliminary data suggest that chronic activation of Akt has deleterious effects associated with feedback inhibition of the signaling molecules IRS-1 and PI 3-kinase (PI3K). These studies suggest that in the absence of PI3K activation, Akt is not sufficient for cardioprotection due to loss of other critical downstream signals. The overall goals of the current proposal are to identify and define the role of Akt-independent cardioprotective mechanisms activated by IGF-I in acute ischemic injury and ventricular remodeling after infarction. This proposal is based on 3 hypotheses: 1) that chronic Akt activation leads to feedback inhibition of IRS-1 and PI3K that contributes to adverse outcomes seen in this setting; 2) that distinct, PI3K-dependent signaling pathways are necessary for full cardioprotection; and 3) that common signaling pathways also modulate ventricular remodeling after infarction. To test these hypotheses, cardiac expression of IGF-I, as well as mutant and wild-type downstream signaling molecules, will be achieved through somatic and germline gene transfer in models of cardiomyocyte death, ischemic injury, and ventricular remodeling. In Specific Aim 1, we will test the hypothesis that feedback inhibition of IRS-1/PI3K accounts for the deleterious effects of chronic Akt activation. In Specific Aim 2, we will identify the Akt-independent mechanisms of cardioprotection responsible for the benefits of IGF-I expression on cardiomyocyte survival and function in vitro and in vivo. In Specific Aim 3, we will test the hypothesis that these pathways also modulate ventricular remodeling after infarction. In Specific Aim 4, we will examine whether gene transfer of optimized cardioprotective effectors can mitigate adverse ventricular remodeling after infarction. Understanding the role of specific pathways in cardiomyocyte survival and learning to locally manipulate these pathways through gene transfer may provide novel therapeutic approaches for the management of acute ischemic injury and ventricular remodeling after infarction.