The causes for congenital valve abnormalities in children are not well understood. Previously we and others have shown that the loss of the GATA4-FOG transcription complex in mice leads to valvular defects. Now our preliminary data shows that the GATA4-FOG transcription complex is required in the developing valve to repress the expression of DKK1, a secreted inhibitor of the canonical Wnt/ss-catenin pathway;mouse mutants with GATA4-FOG complex loss no longer activate valvular canonical ss-catenin signaling. We propose to examine the mechanism of the GATA4-FOG-mediated valvular defect at a genetic and cellular level, and, more broadly, to explore the possibility that at least some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin or ibuprofen could interfere with valvular Wnt/ss-catenin signaling and specifically lead to cardiac valvular defects during mammalian development.
Heart defects are among the most common birth defects in the United States. According to the March of Dimes Foundation web site, heart defects are affecting nearly one in every hundred births (or, more precisely, 8 out of 1000 babies). Moreover, there is an excess of cardiovascular malformations among preterm infants: preterm infants have more than twice as many cardiovascular malformations as do infants born at term and 16% of all infants with cardiovascular malformations are preterm. Valve defects (aortic stenosis, pulmonary stenosis or tricuspid atresia) are among the common birth defects. There are currently no pharmacological approaches to valvular diseases in children. Although surgical procedures or a balloon valvuloplasty became very effective in alleviating even complex heart defects, most patients with these conditions continue to need special heart care throughout their lives. There is a definite genetic component to valvular disease: for pregnant women with congenital heart disease, the risk of their fetus having structural cardiac defects is 3%-12% compared with a risk of 0.8% for the general population. The goal of this proposal is to improve our understanding of both the genetic and toxicological causes for valve defects and to identify the potential risks that could be avoided.
| Brody, Matthew J; Hacker, Timothy A; Patel, Jitandrakumar R et al. (2012) Ablation of the cardiac-specific gene leucine-rich repeat containing 10 (Lrrc10) results in dilated cardiomyopathy. PLoS One 7:e51621 |
| Tevosian, Sergei G; Manuylov, Nikolay L (2008) To beta or not to beta: canonical beta-catenin signaling pathway and ovarian development. Dev Dyn 237:3672-80 |
