Jak/Stat Signaling Pathway in Myocardial Hypertrophy

描述（由申请方提供）：心肌肥大是对血流动力学负荷的适应性反应，继发于血管异常、高血压和瓣膜疾病，被认为是发生充血性心力衰竭的主要风险因素。 最近的实验方法的基础上培养的心脏细胞，离体心脏和基因操作的动物模型，允许识别不同的信号转导途径参与心肌肥大。 然而，诱导细胞肥大的分子机制和信号分子在肥大反应中的确切作用仍然是难以捉摸的。 我们下面的实验旨在验证以下假设：尽管肥大的不同方面涉及多种途径，诱导信号也多种多样，但心脏肥大的根源是一种共同的机制。 我们最近的工作与其他人已经证明，激活的Jak/Stat信号转导通路发生在响应主机的肥大激动剂。 它还揭示了激活的Jak/Stat途径是肥大固有的基因激活程序动员的基础的机制。 这里概述的实验不仅试图暗示激活的Jak 2在肥大中发挥核心作用，而且还将研究它如何将细胞外信号与它们被转导为长期功能反应的机制联系起来。 具体而言，我们将研究（具体目标1）组成型激活Jak 2通过腺病毒介导的表达在培养的心脏细胞中的作用。 同时，我们将研究转基因小鼠和压力超负荷肥大模型中心脏靶向Jak 2表达的影响。 我们还将研究（具体目标2）在体内环境中Jak/Stat信号传导与其他主要途径的组分之间是否存在串扰。 作为具体目标3的一部分，我们将研究压力超负荷性肥大对肾素-血管紧张素系统的需求及其与Jak/Stat通路的联系。 最后，我们将在小鼠中产生Jak 2基因的心脏靶向破坏，试图证明肥大诱导对Jak 2的依赖性。 这些方法有望为心力衰竭的药物干预和基因治疗提供大量有用的信息。

DESCRIPTION (provided by applicant): Myocardial hypertrophy, an adaptation response to hemodynamlc burden, secondary to vascular abnormalities, hypertension and valvular disease, is recognized as a major risk factor for the development of congestive heart failure. The recent experimental approaches based on cultured cardiac cells, isolated heart and genetic manipulation in animal models have allowed the identification of distinct signal transduction pathways involved in myocardial hypertrophy. However, the molecular mechanism(s) by which the cellular hypertrophy is induced and the precise role the signaling molecules play in the hypertrophic response has remained elusive. Our experiments below are designed to test the hypothesis that despite the multiplicity of the pathways involved in different aspects of hypertrophy and the diversity of induction signals, a common mechanism is at the root of cardiac hypertrophy. Our recent work with that of others has documented that activation of the Jak/Stat signal transduction pathway occurs in response to a host of hypertrophic agonists. It has also uncovered a mechanism by which the activated Jak/Stat pathway underlies mobilization of the gene activation program intrinsic to hypertrophy. The experiments outlined here seek not only to implicate the activated Jak2 to play a central role in hypertrophy but will also examine just how it links the extra-cellular signals to the mechanism by which they are transduced into long term functional response. Specifically, we will investigate (Specific aim 1) the role of constitutively activated Jak2 via adenovirus-mediated expression in cardiac cells in culture. In concert, we will examine the effects of the heart targeted Jak2 expression in transgenic mice and in pressure overload hypertrophy models. We will also investigate (Specific aim 2) whether there is a cross talk between the Jak/Stat signaling and the components of other major pathways in an in vivo context. As part of Specific aim 3, we will examine the requirements of the renin-angiotensin system and its linkage to the Jak/Stat pathway in pressure overload hypertrophy. Finally, we will produce the heart-targeted disruption of Jak2 gene in mice in an attempt to demonstrate the dependence of hypertrophy induction upon Jak2. These approaches are expected to provide a wealth of information useful in the generation of targets for drug intervention and gene-based therapy for heart failure.