The long-term goal of this project is to enhance the understanding of molecular mechanisms that control cardiac development and maintenance of a normal cardiac phenotype. Identifying and characterizing the transcription factor cascade that controls cardiac development is an important step in understanding the genesis of congenital heart defects and important clinical disorders such as cardiac hypertrophy and heart failure. Malformations of the heart account for the largest number of human birth defects, about 1 % of live births. Despite this high frequency of occurrence, the molecular mechanisms that lead to congenital heart defects remain poorly understood. We have demonstrated that the phenotype of the mutant mice carrying mutations in the jumonji gene (jmj) is similar to human congenital heart diseases and the fetal form of cardiac failure. Therefore, the proposed research plan is to characterize the developmental and molecular function of jmj and its cofactors in cardiovascular development.
Specific Aim 1. We have identified a putative cofactor of JMJ by yeast two hybrid screening. In this aim, we will test the hypothesis that a novel zinc finger protein (Zfp496) is a cofactor of JMJ, which regulates the molecular function of JMJ.
Specific Aim 2 is to analyze phenotypes of mice harboring a lineage-specific knockout of jmj. We have generated conditional jmj knock out mice in a myocardial-, endothelial-, or neural- specific manner using Cre-loxP technology. In this aim, we will test whether JMJ plays important roles in a cell lineage-specific manner within the developing heart.
Specific Aim 3 is to determine the novel downstream genes of JMJ by microarray analyses. We will investigate global changes in the gene expression profiles by an acute deletion of jmj to identify direct target genes of JMJ and by a chronic deletion to assess the cellular/physiological changes occurred in jmj null hearts. The jmj mutant mouse model is clinically significant, because malformations of the heart account for the largest number of human birth defects and physiological roles of JMJ and cofactors are likely to be conserved in human. Therefore, the outcome of this proposal will yield important insights into both the genesis of congenital heart disease and the mechanisms that lead to cardiac hypertrophy and heart failure.
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