Targeting GRK2 (BARK1) in Heart Failure

在过去的十年中，该R 01/R37已经获得资助，我们已经确定了G蛋白偶联受体（GPCR）激酶2（GRK 2或β ARK 1）的关键作用，不仅在受损/应激心脏中β-肾上腺素能受体信号传导的失调中，而且在独立于GRK 2对GPCR作用的心脏功能中。我们迄今为止从MERIT奖以及正在进行的研究中发表的数据强烈认为GRK 2是心脏损伤和心力衰竭（HF）发病机制的节点调节因子。 我们最初的目的仍然有效，并且被制定为测试中心假设，即GRK 2通过GPCR脱敏以外的机制在病理性肥大、缺血性损伤和HF中起关键作用。我们最初的具体目标是： 具体目标1：确定GRK 2的非GPCR功能是否在GPCR中起促进作用。 适应不良性心肌肥大和LV重构的发病机制。 具体目标2：研究GRK 2在缺血后心肌葡萄糖摄取功能障碍中的作用 并确定GRK 2如何调节葡萄糖代谢和胰岛素信号传导的细胞机制。 具体目标3：确定病毒介导的靶向和沉默GRK 2表达的微小RNA（miGRK 2）的基因转移是否为病理性肥大和缺血性HF提供了新的治疗策略。 在本报告所述期间还剩下两年的时间里，我们将继续进行这些研究，以检验我们的中心假设 并将着手实现三个新的目标，这些目标是上述目标的自然延伸，令人兴奋 新数据揭示的途径。这些新的具体目标是： 具体目标4：确定GRK 2氨基端（RGS结构域）在心肌肥大中的作用。 具体目的5：研究GRK 2（在Ser 670残基处）的MAP激酶调节的机制作用， 通过表征和研究新型GRK 2-S670 A基因敲入小鼠体内。 具体目的6：确定GRK 2在心脏损伤过程中心脏成纤维细胞中的作用。 这些研究将继续阐明心脏中GRK 2生物学作为节点调节器的新方面 和可行的治疗靶点。 相关性（参见说明）： 由于GRK 2的表达水平和活性在包括人心脏在内的衰竭心肌中升高， 失败（HF），使用我们独特的动物模型揭示这种GRK的新机制方面， 分子试剂将导致对肥厚和缺血的发病机制的更广泛的理解， 心功能不全此外，我们描述的翻译研究将证明GRK 2是一个创新的 HF的治疗目标。

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 βARK1) in not only the dysregulation of β-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 instructions): 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 therapeutic target for HF.