The goal of this project will be to advance the understanding of the genetic controls that guide cardiac structural development. Identifying and characterizing the genes involved in this process may be an important step in understanding the genesis of congenital heart defects and in identifying new treatment strategies. For many tissues, homeobox proteins have been demonstrated to be critical for the normal growth and development by regulating target genes in a precise spatial and temporal pattern. The Cardiac-specific homeobox protein, Csx, is required for normal cardiac development; mice lacking this gene die in utero with a very primitive heart tube that has not completed the first phase of structural development, cardiac looping. Therefore, the targets of this gene may direct cardiac growth and development and, when mutated, may cause congenital heart defects. Furthermore, since the Csx gene continues to be expressed in the adult heart, it's target genes may also have a role in the heart's response to hypertension or ischemia. However, to date, no direct target genes of Csx have been identified. In this study, the candidate will use the chromatin precipitation technique and the yeast one hybrid system to identify target genes of the Csx protein. Once target genes have been identified and their regulation by Csx confirmed in vitro, the in vivo significance of this regulation will be examined using transgenic mouse models. Based on these studies, the human homologues of those target genes vital to cardiac development will be identified. In future studies, the role of these genes in the genesis of human congenital heart disease will be examined. As a pediatric cardiologist, the principal investigator is interested in pursuing an independent investigative career studying the genetic controls of myocardial development and characterizing how perturbations of this process cause congenital cardiac defects. The sponsor for this project, Dr. Seigo Izumo, Chief of Cardiology at the University of Michigan, is widely recognized for his work on signal transduction and transcription regulation in cardiac myocytes. His laboratory will provide an excellent environment for advanced training in molecular biology. The University of Michigan, already an active center for molecular biology research, is establishing an Organogenesis Center with core laboratories that will facilitate developmental biology research. Furthermore, the Division of Pediatric Cardiology is creating a repository of cell lines from patients with complex congenital heart defects. In this environment, the principal investigator anticipates acquiring the necessary research skills to contribute to the understanding of cardiac growth and structural development.
| Russell, M W; Kemp, P; Wang, L et al. (1998) Molecular cloning of the human HAND2 gene. Biochim Biophys Acta 1443:393-9 |
