Grant: Operating Grant

In human, cardiac abnormalities represent 25% of congenital malformations, and heart failure is the leading cause of death in industrialized countries. Unfortunately, the cellular and molecular mechanisms controlling cardiac growth and differentiation remain poorly understood. In human and other mammals, the heart is the first functional organ but its development into the mature four-chamber heart is a complex multistep process involving different cell types. The establishment and maintenance of the cardiac phenotype require the activation of cardiac-specific genes in a tightly regulated temporal and spatial manner. This process is governed by the combinatorial action of a limited number of regulatory proteins known as cell-restricted as well transcription factors. Transcription factor GATA-4 has emerged as a key regulator of heart development. Heterozygote mutations in the human GATA4 gene cause congenital heart disease. Our studies are aimed at understanding the essential role of GATA-4 at various stages of heart development and in different cardiac cells. In addition to its crucial role in the embryonic heart, GATA-4 appears to be essential for post-natal myocyte survival and adaptive response to various stressors. Since heart failure is caused by loss of myocytes and impaired responsiveness of the remaining cardiac cells, the GATA-4 pathway may represent a novel target for cardioprotection. We propose to define, at the molecular level, the mechanisms responsible for GATA-4 action in the developing and postnatal heart. Our studies also suggest that another member of the family, GATA-5 is essential for heart valve formation and may be a congenital heart disease causing genes. We propose to further analyze the role of GATA-5 in the heart and its interactions with other heart regulators.