Pp-HEART

Congenital heart diseases (CHD) are the most common type of birth defects, accounting for one third of all major congenital anomalies. CHD define a large set of structural and functional deficits arising during cardiac embryogenesis, the most common forms affecting the outflow or conotruncal region of the heart that gives rise to the aorta and pulmonary trunk, outlets of the left and right ventricles. This conotruncal region of the heart originates from the embryonic outflow tract, derived from Second Heart Field (SHF) progenitor cells in pharyngeal mesoderm. SHF development is regulated by a complex network of transcription factors and signaling pathways and perturbation of these early developmental processes leads to common forms of conotruncal CHD. To date only 30% of CHD has been shown to have a genetic origin and in consequence the importance of environmental causes of CHD, and their intersection with genetic causes, is becoming apparent. Different environmental factors including low oxygen levels, folate deficiency, alcohol exposure and maternal obesity have been shown to impact the conotruncal development in CHD patients and animal models. In this context, our research proposal will explore the intersection between genetic and environmental causes of CHD, in particular maternal obesity, by investigating how genetic and environmental inputs intersect to regulate metabolic programs as SHF progenitor cells differentiate in the embryonic outflow tract. Previously, we have demonstrated that the fatty acid activated transcription factor Peroxisome Proliferator-Activated Receptor gamma (Pparg) is specifically enriched in a subpopulation of SHF cells as they differentiate in the distal outflow tract. Preliminary evidence obtained in wildtype and conditional mutant embryos demonstrates that Pparg is required in the SHF for early heart tube development and that induced maternal obesity results in CHD in mouse models. The focus of the Pp-HEART project rests on these results which provide a novel entry point for studies of genetic and environmental interactions during heart tube development. We propose that the lipid sensor PPAg is a critical regulator of metabolic status during the differentiation of SHF progenitor cells and that maternal obesity is responsible for abnormal metabolic changes in the SHF leading to CHD. In the Pp-HEART project we will address Pparg regulation in cardiac progenitors, using unique mouse genetic models and state of the art experimental approaches such as ex vivo culture of embryos/explants, imaging, mitochondria bioenergetics and high throughput RNA-Seq. Our project will use state of art quantitative approaches to provide the first metabolic profile of differentiating SHF cells during early heart development under wildtype, mutant and high fat conditions. Together these approaches will identify new critical PPARg functions, as well as regulatory genes and metabolic pathways governing SHF deployment and heart morphogenesis. A major strength of the Pp-Heart project is that it combines for first time complementary areas of expertise of cardiac biologists in development and energy metabolism and unique mouse models to focus on an unexplored area of early heart development. We anticipate that our results will contribute new knowledge concerning the etiology of CHD in relation to environmental risk factors such as maternal obesity and ultimately identify relevant targets in the diagnosis and prevention of life-threatening CHDs.