Jak/Stat Signaling Pathway in Myocardial Hypertrophy

说明(申请人提供)：心肌肥厚是一种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，被认为是发展为充血性心力衰竭的主要危险因素。最近基于培养的心肌细胞、分离的心脏和动物模型中的基因操作的实验方法使得识别与心肌肥大有关的不同的信号转导途径成为可能。然而，诱导细胞肥大的分子机制(S)以及信号分子在肥大反应中所起的确切作用仍然不清楚。我们下面的实验旨在检验这一假设，即尽管肥厚的不同方面涉及的途径多种多样，诱导信号也不同，但一个共同的机制是心肌肥厚的根源。我们最近与其他人的工作证明，JAK/STAT信号转导通路的激活是对一系列肥大激动剂的反应。它还揭示了一种机制，即激活的JAK/STAT通路是肥大固有基因激活程序动员的基础。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，而且还将检查它如何将细胞外信号与这些信号转化为长期功能反应的机制联系起来。具体地说，我们将研究(特定目标1)通过腺病毒介导的JAK2在培养的心肌细胞中表达而激活的JAK2的作用。同时，我们将研究心脏靶向JAK2在转基因小鼠和压力超负荷肥厚模型中的表达效果。我们还将调查(特定目标2)在活体环境中，JAK/STAT信号与其他主要通路的组成部分之间是否存在串扰。作为特定目标3的一部分，我们将研究压力超负荷性肥厚对肾素-血管紧张素系统的要求及其与JAK/STAT通路的联系。最后，我们将在小鼠中产生心脏靶向的JAK2基因的破坏，试图证明肥大诱导对JAK2的依赖性。这些方法有望为心力衰竭的药物干预和基于基因的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.