Characterization of the ß-Adreno Receptor Kinase 1 (ßARK1) as a Novel Therapeutic Target in Heart Failure using Conditional and Tissue-Specific Knockout Mice

G蛋白偶联受体激酶（GRKs）的作用关键地调节β-肾上腺素能受体（β AR）信号传导。在心血管系统中，β AR信号通路控制心脏的重要反应，例如收缩能力（变力性）和收缩更快的能力（变时性）。观察到β AR激酶1（β ARK 1或GRK 2）在与心功能受损相关的心血管疾病中显著增加，表明该分子在心力衰竭（HF）的情况下可能具有主要的病理生理学相关性。研究β ARK 1的病理生理作用的独特模型是敲除小鼠。由于传统的β ARK 1-/-小鼠是胚胎致死的，因此需要替代策略来研究β ARK 1表达缺失在成年心脏中的功能后果。条件性敲除策略将最大限度地减少发育问题，更重要的是，<$ARK1基因消融可以按需进行，并且仅在心脏中进行。为了产生这些小鼠，将使用Cre-loxP技术。第一种方法被设计为在发育调节（出生后）程序中使用MHC-Cre小鼠仅在心脏中有条件地敲除β ARK 1基因。第二种策略设计为使用他莫昔芬（Tmx）诱导的MHC-Cre小鼠按需破坏和消融心脏中的β ARK 1基因。因此，可以研究在任何时候心脏中β ARK 1完全（或50%）缺失的后果。在这些小鼠中诱导HF将测试β ARK 1消融是否可以防止HF的发展（<$MHC-Cre小鼠）或在衰竭心脏中β ARK 1的损失是否会导致心脏性能的改善（Tmx诱导的<$MHC-Cre小鼠）。这些小鼠提供了独特的机会来测试β ARK 1消融作为治疗心力衰竭的新疗法的最终作用，即预防和/或挽救。

The actions of G-protein coupled receptor kinases (GRKs) critically regulate beta-adrenergic receptor (ßAR) signaling. In the cardiovascular system, the ßAR signaling pathway controls important responses of the heart such as the ability to contract (inotropy) and the ability to contract faster (chronotropy). The observation that the ßAR kinase 1 (ßARK1 or GRK2) is increased significantly in cardiovascular disease associated with impaired cardiac function, suggests that this molecule could have major pathophysiological relevance in the setting of heart failure (HF). A unique model to investigate the pathophysiological role of ßARK1 is the knockout mouse. Since conventional ßARK1-/- mice are embryonic lethal, alternative strategies are needed in order to study the functional consequences of a loss of ßARK1 expression in the adult heart. Conditional knockout strategies will minimize developmental problems and more importantly, ßARK1 gene ablation can occur ¿on demand¿ and only in the heart. To generate these mice Cre-loxP technology will be utilized. The first approach is designed to conditionally knockout the ßARK1 gene only in the heart using ¿MHC-Cre mice in a developmentally regulated (post-natal) program. The second strategy is designed to disrupt and ablate the ßARK1 gene only in the heart on demand using tamoxifen (Tmx)- inducible ¿MHC-Cre mice. Thus, the consequence of the complete (or 50%) loss of ßARK1 in the heart at any time can be studied. Induction of HF in these mice will test whether ßARK1 ablation can prevent the development of HF (¿MHC-Cre mice) or the loss of ßARK1 in a failing heart will lead to improvement in cardiac performance (Tmx-inducible ¿MHC-Cre mice). These mice offer the unique opportunity to test the ultimate role of ßARK1 ablation as a novel therapy in the treatment of heart failure, i.e. prevention and/or rescue.