Congenital heart disease (CHD) is the most common birth defect in humans, occurring with a frequency of nearly 1 in 100 live births and 1 in 10 first trimester miscarriages, yet the etiology remains unknown. The long-term goals of my laboratory are to dentify molecular pathways regulating cardiogenesis in the interest of understanding the bases of congenital heart disease. Because CHD affects specific segments of the heart, we have searched for chamber-specific regulatory pathways that function during cardiac development. Our studies have shown that dHAND and eHAND are related basic helix-loop-helix (bHLH) transcription factors that are expressed in a complementary fashion in the right and left ventricles, respectively, of the mouse heart. Mice lacking dHAND have a hypoplastic right ventricle and cardiac neural crest cell defects from excessive apoptosis, although early cardiac failure precluded identification of independent roles for dHAND in specific tissues. Inquiries into how segmental gene expression is established in the heart led to the discovery of a novel subclass of cardiac bHLH proteins sharing homology with dHAND. These proteins (HRTI, HRT2, HRT3) belong to the Hairy family of transcription factors that mediate Notch signaling. HRTI and HRT2 are expressed specifically in the atria and ventricles of the heart, respectively, providing an entry to understand atrial vs. ventricular-specific gene expression. This proposal seeks to define the molecular cascades regulating chamber-specific cardiac development through the study of bHLH networks during cardiogenesis.
The specific aims are: 1) To define the tissue-specific functions of dHAND during embryonic development using conditional gene deletion in mice; 2) To determine the genetic interactions between dHAND and eHAND and their functional redundancy by intercrossing dHAND and eHAND mutant mice and by placing eHAND into the dHAND locus by homologous recombination; 3) To determine if the HRT proteins function downstream of Notch signaling in tissue culture and genetically altered mice; 4) To understand whether HRT-related pathways regulate segmental cardiac and vascular development through targeted gene deletion. These studies will provide insights into the mechanisms of segmented gene regulation during cardiac morphogenesis that may ultimately allow for preventive interventions for CHD.
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