Signaling mechanisms of cardioprotection and remodeling

描述(由申请人提供)：心肌细胞死亡在许多临床重要的心脏疾病中被发现，包括心力衰竭、缺血性损伤和梗死后的心室重构。在急性心脏损伤和慢性重构模型中，IGF-I的急性和慢性表达具有心脏保护作用。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的许多效应，但我们的初步数据表明，Akt的慢性激活与信号分子IRS-1和PI3K(PI3K)的反馈抑制有关。这些研究表明，在没有PI3K激活的情况下，Akt不足以起到心脏保护作用，因为失去了其他关键的下游信号。本提案的总体目标是确定和确定由IGF-I激活的Akt非依赖性心脏保护机制在急性缺血性损伤和脑梗塞后心室重塑中的作用。这一建议基于3个假设：1)慢性Akt激活导致IRS-1和PI3K的反馈抑制，从而导致在这种情况下看到的不良结果；2)不同的，PI3K依赖的信号通路是完全心脏保护所必需的；以及3)共同的信号通路也调节梗死后的心室重构。为了验证这些假说，将通过体细胞和生殖系基因转移来实现心肌IGF-I以及突变型和野生型下游信号分子在心肌细胞死亡、缺血性损伤和心室重构模型中的表达。在具体目标1中，我们将检验这样的假设，即IRS-1/PI3K的反馈抑制解释了慢性Akt激活的有害影响。在特定的目标2中，我们将确定IGF-I表达对体外和体内心肌细胞存活和功能的益处的非Akt依赖的心肌保护机制。在特定的目标3中，我们将检验这一假设，即这些通路也调节心肌梗死后的心室重构。在特定的目标4中，我们将检验优化的心脏保护效应器的基因转移是否可以减轻心肌梗死后的不良心室重构。了解特定通路在心肌细胞存活中的作用，并学会通过基因转移在局部操纵这些通路，可能为治疗急性缺血性损伤和心肌梗死后的心室重构提供新的治疗途径。

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.