The experiments in this application are designed to examine the effects of retinoic acid (RA) on myocardial development and to isolate and identify retinoid sensitive target genes that are involved in cardiogenesis. Nutritional studies identified a distinct set of cardiovascular anomalies associated with vitamin A deficiency, and interestingly, similar cardiac defects are also seen in vitamin A excess. Although the cardiogenic neural crest is a well characterized target affected by RA, the effects of vitamin A on the myocardium have been less well characterized. The investigators propose to establish new transgenic models to study the effects of cardiac restricted retinoid deficiency and excess. They will target transgenic expression to the myocardium during early cardiogensis by using the B myosin heavy chain (BmyHC) gene promoter. To reproduce a retinoid deficient state, they will use dominant negative retinoid receptors to interfere with retinoid medicated signaling. To mimic retinoid excess, they will use a constitutively active receptor that functions in the absence of exogenous ligand. The facility with which RA reproduces cardiac defects provides the means to examine the morphogenetic process associated with these malformations as well as the underlying molecular mechanisms. Although the mechanism of action of RA has been intensively studied, only a handful of target genes have been identified which respond to RA. Fewer still have been specifically linked with cardiogenesis. To identify RA sensitive target genes they propose to use a gene trapping strategy in embryonic stem (ES) cells and to screen responsive clones in embryoid bodies (EB)s. These genes will then be cloned from the RA-responsive ES cells, sequenced and their expression characterized in the transgenic models they establish. Together these experiments will establish well defined animal models with retinoid-associated cardiovascular defects and will identify unique sets of retinoid sensitive genes that are active during cardiogenesis. This application will lay the ground work and generate a set of novel reagents that will facilitate dissection of the molecular mechanisms involved in cardiac development.
| Hall, D G; Morley, G E; Vaidya, D et al. (2000) Early onset heart failure in transgenic mice with dilated cardiomyopathy. Pediatr Res 48:36-42 |
| Colbert, M C; Hall, D G; Kimball, T R et al. (1997) Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice. J Clin Invest 100:1958-68 |
