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

• Applicant: Dr. Philip Raake
• Subject Area: Cardiology, Angiology
• Term: from 2006 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 28996692

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Walter J. Koch