TARGETING BETAARK1 IN HEART FAILURE: Myocardial Beta-adrenergic receptors (BETAARs) play a fundamental role in the pathology of heart failure (HF). Signaling through these receptors can be dampened by the actions of the BETAAR kinase (BETAARK1), which phosphorylates agonist- occupied BETAARs leading to attenuation of signaling and homologous desensitization. A significant body of evidence is accumulating which demonstrates that the action of BETAARK1 is extremely important in modulating cardiac function both under normal conditions and in HF. Recent studies have shown that BETAARK1 expression and activity are elevated in a variety of cardiovascular disorders including chronic human HF which can contribute to HF pathology. In a series of studies involving genetically altered mice, it was shown that altering myocardial BETAARK1 activity can significantly affect myocardial function and development. Importantly, the inhibition of BETAARK1 has led to enhanced myocardial contractility and performance in mouse models. This proposal is based on a recent discovery that the cardiac- targeted expression of a BETAARK1 inhibitor transgene could reverse the cardiomyopathic phenotype seen in a genetic mouse model of human HF. Thus, this proposal is formulated to test the Central Hypothesis that BETAARK1 is a primary factor involved in the development of HF and to specifically address the role of inhibition of this kinase as a novel therapeutic strategy to treat this devastating disease process. Associated Specific Aims are: [1] To determine if enhanced myocardial BETAARK1 activity can accelerate the development of cardiomyopathy by generating novel hybrid gene-targeted mice. [2] To determine the physiological role of BETAARK1 in adult cardiac function and the functional impact of the complete loss of myocardial BETAARK1, novel conditional tissue- and timed- specific gene-targeted mice will be generated where the BETAARK1 gene will be """"""""knocked out"""""""" only in the heart either at birth or """"""""on demand"""""""". [3] To determine whether BETAARK1 is critically involved in the development of HF, the conditional knockout mice generated and comprehensively characterized above will be crossed with genetic mouse models of HF described in this collaborative R01. [4] To determine if specific BETAARK1 inhibition can be achieved in the hearts of transgenic mice by generating and comprehensively characterizing animals overexpressing a catalytic dominant-negative mutant or an amino terminal peptide and to see if these mice can rescue the genetic mouse model of human HF described above. The current proposal, combined with the other components of this collaborative R01, provide a unique opportunity to understand the relationship between BETAAR signaling, excitation-contraction coupling and cell survival in the development of cardiomyopathy and HF.
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