Investigation of Human Antigen R (HuR) as a Novel Mediator of Cardiac Hypertrophy

 描述(申请人提供)：我研究的长期目标是增加我们对促进病理性心肌肥厚发生发展的分子机制的了解。为了追求这一目标，我的实验室有新的数据表明，RNA结合蛋白人类抗原R(HUR)是一种新的病理性心肌肥厚的介体。HUR在促肥大信号介质如苯肾上腺素和血管紧张素的下游被激活，尽管它在心肌细胞中高表达，但对HUR在心脏中的功能作用知之甚少。来自我的实验室的新的初步数据表明，HUR在肥大的心肌细胞中被激活，心脏特异性的HUR的缺失防止了对压力超负荷的病理性肥大的反应。因此，我们的中心假设是，心肌细胞中Hur的激活促进了病理性心肌肥厚，而消融Hur则具有保护作用。目的1确定Hur在病理性心肌肥厚中的功能影响及其下游信号转导途径。其工作假设是，心脏特异性Hur缺失小鼠在横动脉缩窄(TAC)后，与从代偿状态到去代偿状态转变相关的病理性肥厚和心脏重塑的发展将会减少。我们已经开发出一种可诱导的心脏特异性Hur缺失小鼠，它将使我们能够在最初的肥厚刺激前后检查Hur缺失的临床相关场景，以确定在稍后的时间点阻断Hur是否可以延缓或挽救肥厚到心力衰竭的病理进展。目的2将确定导致心肌细胞Hur激活的上游信号通路，并确定Hur在GQ介导的肥大中的功能影响。工作假设是，HUR是GQ偶联GPCR诱导的病理性肥大的一种新的下游信号媒介。Gq蛋白的激活几乎见于各种形式的病理性肥厚，但其激活导致心脏病理改变的具体机制尚未完全阐明。因此，我们的结果将对我们如何理解病理性肥厚产生重大影响，HUR作为肥大心肌细胞GQ激活下游的关键信号节点。我们建议的研究将确定Hur在病理性肥大发生发展中的功能作用，并确定Hur在肥大心肌细胞中的下游靶点(目标1)。我们还将确定肥厚心脏中HUR被激活的上游机制，并确定HUR是GQ依赖性病理性肥厚的新介质(目标2)。这项工作具有临床意义，因为我们将确定直接抑制HUR是否具有作为预防或治疗病理性肥厚的治疗靶点的翻译价值。

 DESCRIPTION (provided by applicant): The long-term goals of my research are to increase our understanding of the molecular mechanisms that promote the development and progression of pathological cardiac hypertrophy. In pursuit of this goal, my laboratory has new data suggesting the RNA binding protein Human antigen R (HuR) is a novel mediator of pathological cardiac hypertrophy. HuR is activated downstream of pro-hypertrophic signaling mediators such as phenylephrine and angiotensin, and although it is highly expressed in cardiac myocytes, very little is known concerning the functional role of HuR in the heart. New preliminary data from my lab shows that HuR is activated in hypertrophic myocytes, and cardiac-specific deletion of HuR prevents pathological hypertrophy in response to pressure overload. Thus, our central hypothesis is that activation of HuR in the cardiac myocytes promotes pathological cardiac hypertrophy, while ablation of HuR is protective. Aim 1 will determine the functional impact and downstream signaling of HuR in pathological cardiac hypertrophy. The working hypothesis for is that development of pathological hypertrophy and the cardiac remodeling associated with the transition from the compensated to de-compensated state will be reduced in cardiac-specific HuR deletion mice following transverse aortic constriction (TAC). We have developed an inducible cardiac-specific HuR deletion mouse that will allow us to examine the clinically relevant scenario of HuR deletion before and after the initial hypertrophic stimulus to determine whether blockade of HuR at a later time point can and delay or rescue pathological progression of hypertrophy to heart failure. Aim 2 will identify the upstream signaling pathways that lead to HuR activation in myocytes and determine the functional impact of HuR in Gq-mediated hypertrophy. The working hypothesis is that HuR is a novel downstream signaling mediator of Gq-coupled GPCR-induced pathological hypertrophy. Activation of Gq-protein is observed in nearly every form of pathological hypertrophy, but the specific mechanisms by which its activation results in cardiac pathology have yet to be fully elucidated. Thus, our results are poised to make a significant impact in how we understand pathological hypertrophy with HuR as a key signaling node downstream of Gq activation in the hypertrophic myocyte. Our proposed studies will determine the functional role of HuR in the development and progression of pathological hypertrophy and identify the downstream targets of HuR in hypertrophic myocytes (Aim 1). We will also determine the upstream mechanisms by which HuR is activated in the hypertrophic heart and identify HuR as a novel mediator of Gq-dependent pathological hypertrophy (Aim 2). This work is clinically significance in that we will determine whether direct inhibition of HuR has translational value as a therapeutic target for the prevention or treatment of pathological hypertrophy.