The complementary use of human genetics and model systems to understand disease-causing genes and the mechanisms that lead to disease holds great promise. A small number of genes causing congenital cardiovascular malformations (CCVMs) have been identified using genomewide linkage analysis in affected pedigrees, including the gene encoding a transcription factor, GATA4. In contrast to the limited number of genes identified through human studies, the recognition that key regulatory programs of cardiogenesis are conserved across species has led to the identification of over one hundred genes that, when mutated in model systems ranging from fruit flies to mice, cause defects in cardiac development. Approximately half are transcription factors. However, the contribution of genes encoding transcription factors to CCVMs and the precise mechanisms through which most of the essential genes function are largely unknown. In preliminary data, the PIs have undertaken a large-scale effort designed to translate the basic discoveries of the last decade into an understanding of the molecular basis of CCVMs. A screen of 60 patients with CCVM for sequence variations in 100 cardiac developmental genes resulted in identification of significant gene mutations in nearly half of all patients studied with at least one-third having demonstrable function-altering mutations. The PIs hypothesize that many of the human mutations in cardiac transcription factors significantly affect protein function and are likely to predispose to disease. In this project, they will test the hypothesis stated above for selected transcription factor mutations that are likely to be critical for human cardiogenesis. Specifically, they will build on the existing strengths of their lab and focus on the significance of human mutations in the hairy-related transcription factor, HRT2, GATA4 and the potent transcriptional activator, Myocardin (MYCD). By utilizing numerous available assays, the PIs will determine the mechanisms through which human mutations in these genes affect protein function in vitro and cardiogenesis in vivo, using both mouse and frog systems. Such studies will not only provide insight into the relevance of the human mutations, but will also reveal important structure-function aspects regarding the biology through which the cardiac regulatory proteins operate.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHD1-RRG-K (24))
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Schramm, Charlene A
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Yu, Sangho; Crawford, Dianna; Tsuchihashi, Takatoshi et al. (2011) The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling. Dev Dyn 240:384-93
Tsuchihashi, Takatoshi; Maeda, Jun; Shin, Chong H et al. (2011) Hand2 function in second heart field progenitors is essential for cardiogenesis. Dev Biol 351:62-9
King, Isabelle N; Qian, Li; Liang, Jianping et al. (2011) A genome-wide screen reveals a role for microRNA-1 in modulating cardiac cell polarity. Dev Cell 20:497-510
Ieda, Masaki; Fu, Ji-Dong; Delgado-Olguin, Paul et al. (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375-86
Maitra, Meenakshi; Koenig, Sara N; Srivastava, Deepak et al. (2010) Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res 68:281-5
van Laake, Linda W; Qian, Li; Cheng, Paul et al. (2010) Reporter-based isolation of induced pluripotent stem cell- and embryonic stem cell-derived cardiac progenitors reveals limited gene expression variance. Circ Res 107:340-7
Cordes, Kimberly R; Srivastava, Deepak (2009) MicroRNA regulation of cardiovascular development. Circ Res 104:724-32
Fish, Jason E; Srivastava, Deepak (2009) MicroRNAs: opening a new vein in angiogenesis research. Sci Signal 2:pe1
Kwon, Chulan; Qian, Li; Cheng, Paul et al. (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11:951-7
Nigam, Vishal; Srivastava, Deepak (2009) Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol 47:828-34

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