Abnormalities of cardiac development underlie a host of important disorders from the in utero malformations seen in congenital heart disease, to the gradual loss of contractile function seen in idiopathic dilated cardiomyopathy. The long term goal of this project will be to understand the molecular genetics and cellular interactions underlying cardiac formation and development. The investigation will center on the embryologic and genetic analysis of vertebrate heart formation and cardiac function in the zebrafish, Brachydanio rerio, a freshwater teleost uniquely suited for such investigations. A central focus of the project will be to determine at what point cells of the cardiac primordia are fated to become a specific tissue in the mature heart (ventricle vs. atrium, myocardium vs. endocardium), and what are the external and internal signals that lead to that determination. The first stage of investigation will be to label blastomeres of the cardiac primordia just prior to gastrulation and map the fate of the cell's clonal progeny. Due to the transparency of zebrafish embryos, single cells can be efficiently marked with non-toxic lineage dyes and cell migration and differentiation can be observed throughout development. Through this map of cell fate for cardiac primordia it will be determined at what point cell lineage of precursor cells is restricted to specific structures. The next phase of investigation will involve analyzing zebrafish mutants with defects in cardiac development and cardiac morphogenesis. Two mutants are currently available at the Massachusetts General Hospital Cardiovascular Research Center (CVRC) with defects in cardiac contractility, and large scale screening programs are currently in place in the CVRC and other laboratories worldwide. My initial studies will focus on the analysis of the """"""""silent heart"""""""" mutation in which homozygous embryos develop a heart which is morphologically normal but which does not beat. Preliminary data suggests the defect involves the contractile proteins, and in particular troponin. This hypothesis will be evaluated using RFLP linkage analysis. As a training program, through this project I will gain facility in two important classical disciplines, embryology and genetics, and I will be well positioned to apply them as a physician-scientist to the study of cardiovascular disease.
| McNamara, D M; Holubkov, R; Janosko, K et al. (2001) Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation 103:1644-8 |
