Jak/Stat Signaling Pathway in Myocardial Hypertrophy

描述（由申请人提供）：心肌肥大是对血流动力学负担的适应性反应，继发于血管异常、高血压和瓣膜疾病，被认为是发展为充血性心力衰竭的主要危险因素。最近的实验方法基于培养的心脏细胞，分离的心脏和动物模型的遗传操作，已经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以及信号分子在肥大反应中所起的确切作用仍然是未知的。我们下面的实验旨在验证这样一个假设：尽管肥厚的不同方面涉及的途径多种多样，诱导信号也多种多样，但一个共同的机制是心脏肥厚的根源。我们最近和其他人的研究表明，Jak/Stat信号转导通路的激活发生在对大量肥厚受体激动剂的反应中。它还揭示了激活的Jak/Stat通路在肥大固有的基因激活程序动员的基础上的机制。这里概述的实验不仅试图暗示激活的Jak2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成长期功能反应的机制联系起来。具体来说，我们将研究（Specific aim 1）在培养的心脏细胞中通过腺病毒介导表达组成型激活Jak2的作用。同时，我们将在转基因小鼠和压力过载肥大模型中研究心脏靶向Jak2表达的影响。我们还将研究（具体目标2）在体内情况下，Jak/Stat信号和其他主要通路的成分之间是否存在串扰。作为特定目标3的一部分，我们将研究肾素-血管紧张素系统的需求及其与压力过载肥厚中Jak/Stat通路的联系。最后，我们将在小鼠中产生Jak2基因的心脏靶向破坏，试图证明肥厚诱导依赖于Jak2。这些方法有望为心衰药物干预和基因治疗靶点的产生提供丰富的有用信息。

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.