 |
 |
Chrissa Kioussi
Associate Professor, College of Pharmacy
|
 |
||||||||||||||
RESEARCH:
Signaling Pathways in Cardiovascular Development
The precision in formation of a developing embryo is the result of an intricate mechanism of morphogenetic events including cell growth, proliferation, differentiation, and cell death. These spatiotemporal events bring cell populations together for interactions to form three dimension structures. At the molecular level, complex cascades of signal transduction pathways coupling with an overlapping array of transcription factors constitute the basis for interpreting the transient morphogenetic code. Parallel events and similar molecular mechanisms are used repetitively with slight variations in the development and regulation of multiple organs and tissues. Impressive advances have begun to elucidate the mystery of congenital heart disease at the molecular level. In addition, the molecular pathways emerging from the study of cardiac development are being applied to the understanding of adult cardiac disease. Gene targeting technology brings an exciting and powerful new approach to the study of congenital heart disease and human syndromes. Using the tools of embryonic stem cell manipulation and homologous recombination, specific mutations into any gene within the mouse genome can be engineered. In addition with the recent advances in transgenic mouse technology the function of specific genes can be analyzed at specific time and in specific tissues by using site-specific recombinases.
The bicoid-related Pitx genes have provided an ideal model for investigating this molecular development because their deletion causes a failure of cell type-specific proliferation in several organs at specific stages of organogenesis. Pitx2, a gene that causes Rieger syndrome, executes the asymmetric morphogenesis of the primordia of all visceral organs. It acts via distinct regulatory regions downstream of the nodal signaling pathway. In Pitx2 gene-deleted mice, the development of the cardiovascular system is altered. With respect to cardiac outflow tract development, there is a genetic linkage between Pitx2 and Dvl2, a gene encoding a critical signaling molecule in the Wnt pathway. Wnt/Dvl2, via GSK-3/ß-catenin, activates Pitx2, which in turn regulates targets that include growth-regulating genes. Studing the molecular mechanisms by which transcription factors such as the homeobox genes Pitx2 and Pax3 mediate these events during normal development, their relationships with other factors and their potential combinatorial roles in cardiovascular and muscle development will give important insights for understanding development and disease. Examination of the functional role of co-activators or co-repressors in cardiogenesis is an ideal paradigm for the analysis of the determinative events that govern the decision of the cell to divide or differentiate.