Pediatric cardiologists commonly see patients whose diseases suggest defects in the development of the atrioventricular (AV) conduction system, but the molecular mechanisms of normal and hence abnormal development are poorly understood. Recently, mutations of the cardiac homeobox gene, Nkx2.5, were found to cause AV block in isolation or in association with congenital heart defects in humans and mice. Nkx2.5 regulates the expression of several important transcription factors during cardiac development. One of these is Msx2, which is expressed by the primordial conduction system and is abnormally expressed in homozygous null mutant mouse hearts. The specific experimental aims of this proposal are to examine the roles of Msx2 in normal and abnormal cardiac conduction system development in mice that have knockout or transgenic mutations of Msx2 or Nkx2.5, to elucidate the regulatory mechanisms of Msx2 expression in the chick embryo system, and to characterize further the conduction defect observed in Nkx2.5 mutant mice. The results may suggest new insights into the development of the conduction system and the pathogenesis of cardiac arrhythmias, a leading cause of morbidity and mortality in the United States. Through this research proposal, the applicant will receive training in molecular and developmental biology and animal models of cardiac development and physiology. Through the guidance of the two physician-scientist sponsors and work with collaborators the applicant will gain the necessary skills and knowledge to become an independent investigator in the field of cardiac development.
