Signaling mechanisms of cardioprotection and remodeling

描述（由申请人提供）：在许多临床重要的心脏疾病中发现了心肌细胞死亡，包括心力衰竭、缺血性损伤和梗死后心室重塑。IGF-I的急性和慢性表达在急性心脏损伤和慢性重塑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PI 3-激酶（PI 3 K）的反馈抑制相关的有害作用。这些研究表明，在没有PI 3 K激活的情况下，Akt由于其他关键下游信号的丢失而不足以用于心脏保护。目前的建议的总体目标是确定和定义的作用Akt的非依赖性的心脏保护机制激活IGF-I急性缺血性损伤和心室重构梗死后。该提议基于3个假设：1）慢性Akt激活导致IRS-1和PI 3 K的反馈抑制，这有助于在这种情况下观察到的不良结果; 2）不同的PI 3 K依赖性信号通路对于完全的心脏保护是必要的; 3）共同的信号通路也调节梗死后的心室重塑。为了验证这些假设，IGF-I以及突变型和野生型下游信号分子的心脏表达将通过心肌细胞死亡、缺血性损伤和心室重塑模型中的体细胞和种系基因转移来实现。在具体目标1中，我们将检验IRS-1/PI 3 K的反馈抑制解释慢性Akt激活的有害作用的假设。在具体目标2中，我们将确定Akt独立的心脏保护机制，负责IGF-I表达对体外和体内心肌细胞存活和功能的益处。在具体目标3中，我们将检验这些通路也调节梗死后心室重构的假设。在具体目标4中，我们将研究优化的心脏保护效应物的基因转移是否可以减轻梗死后的不利心室重构。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局部操纵这些通路，可能为急性缺血性损伤和梗死后心室重塑的管理提供新的治疗方法。

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.