Targeting GRK2 (BARK1) in Heart Failure

在过去的十年里，R01/R37得到了资助，我们定义了G蛋白偶联的关键作用 受体(GPCRK)2(GRK2或pARK1)不仅在β-肾上腺素能受体信号转导中的失调 在损伤/应激的心脏中，也在心功能上独立于GRK2的S的作用 GPCRs。到目前为止，我们公布的数据来自这个功勋奖以及正在进行的研究 强烈支持GRK2是心脏损伤和心力衰竭(HF)发病机制的结节调节因子。 我们最初的目标仍然有效，并且是为了检验GRK2发挥关键作用的中心假设而制定的 通过GPCR脱敏以外的机制在病理性肥厚、缺血性损伤和心力衰竭中发挥作用。我们的 最初的具体目标是： 具体目标1：确定GRK2的非GPCR功能是否在 适应性不良的心肌肥厚和左室重构的发病机制。 特异目的2：探讨GRK2在缺血后心肌葡萄糖摄取障碍中的作用 并确定GRK2如何调节葡萄糖代谢和胰岛素信号的细胞机制。 具体目标3：确定病毒介导的微RNA基因转移是否针对和 沉默GRK2表达(MiGRK2)为病理性肥厚和高血压提供了新的治疗策略。 缺血性心力衰竭。 在当前时期剩下的两年时间里，我们将继续进行这些研究，以检验我们的中心假设 还将着手三个新目标，这三个目标是上述目标的自然延伸，令人兴奋 新数据揭示的道路。这些新的具体目标是： 具体目的4：确定GRK2氨基末端(RGS结构域)在心肌肥厚中的作用。 特异目的5：研究GRK2(At残基Ser670)对MAPK的调节机制 体内通过鉴定和研究一种新型的GRK2-S670A敲入小鼠。 特定目的6：确定GRK2在心脏损伤时心脏成纤维细胞中的作用。 这些研究将继续阐明GRK2生物学在心脏中作为结节调节因子的新方面 发病机制和可行的治疗靶点。 相关性(请参阅实例)： 由于GRK2在衰竭心肌中的表达水平和活性升高，包括在人类心脏中 失败(HF)，揭示了GRK的新机制方面，使用我们独特的动物模型和 分子试剂将使人们对肥厚和缺血的发病机制有更广泛的了解 心脏功能不全。此外，我们所描述的翻译研究将证明GRK2是一种创新的 治疗心力衰竭的Taraftt疗法

Over the last decade+ that this R01/R37 has been funded, we have defined a key role for G protein-coupled receptor (GPCR) kinase 2 (GRK2 or pARK1) in not only the dysregulation of p-adrenergic receptor signaling in the injured/stressed heart but also in cardiac functions that are independent from GRK2's actions on GPCRs. The data that we have published to date from this MERIT Award as well as ongoing research strongly argue for GRK2 being a nodal regulator of cardiac injury and pathogenesis of heart failure (HF). Our original Aims are still valid and are formulated to test the Central Hypothesis that GRK2 plays a critical role in pathological hypertrophy, ischemic injury and HF via mechanisms beyond GPCR desensitization. Our original Specific Aims are: Specific Aim 1: To determine whether non-GPCR functions of GRK2 play a facilitative role in the pathogenesis of maladaptive cardiac hypertrophy and LV remodeling. Specific Aim 2: To investigate the role of GRK2 in dysfunctional myocardial glucose uptake after ischemia and to determine the cellular mechanisms of how GRK2 regulates glucose metabolism and insulin signaling. Specific Aim 3: To determine whether viral-mediated gene transfer of a micro-RNA that targets and silences GRK2 expression (miGRK2) offers a novel therapeutic strategy for pathological hypertrophy and ischemic HF. With the two years left on the current period we will continue these studies testing our central hypothesis and will also embark on three new aims that are natural extensions of the above Aims and are exciting avenues uncovered by new data. These new Specific Aims are: Specific Aim 4: To determine the role of the amino-terminus (RGS domain) of GRK2 in cardiac hypertrophy. Specific Aim 5: To study the mechanistic role of MAP kinase regulation of GRK2 {at residue Ser670) in vivo through characterization and study of a novel GRK2-S670A knock-in mice. Specific Aim 6: To determine the role of GRK2 in the cardiac fibroblast during cardiac injury. These studies will continue to elucidate novel aspects of GRK2 biology in the heart as a nodal regulator of pathogenesis and a viable therapeutic target. RELEVANCE (See instnjctions): Since expression levels and activity of GRK2 are elevated in failing myocardium including in human heart failure (HF), uncovering novel mechanistic aspects of this GRK using our unique animal models and molecular reagents will lead to a broader understanding of the pathogenesis of hypertrophic and ischemic cardiac dysfunction. Moreover, our translational studies described will prove that GRK2 is an innovative theraneutic taraftt for HF