Congenital heart diseases account for the highest frequency of human birth defects, affecting 1 in 1000 live births. In an effort to gain a better understanding of congenital heart diseases in the human population, the goals of this study are to define the molecular mechanisms controlling cardiac cell specification and differentiation using vertebrate models. The break down in these molecular networks are the ultimate cause of congenital heart diseases and gaining an understanding of the transcription factors controlling cardiogenesis will facilitate the development of better screens and treatments. To date, no heart-specific transcription factors have been identified, implying that cardiac-specific transcriptional regulation occurs via multiprotein complexes and thus understanding how transcription factors regulate their protein-protein interactions is required for understanding cardiac specific transcription. The HAND class of bHLH transcription factors, HAND1 and HAND2, are expressed at the earliest stages of heart formation across species. Gene disruption experiments of the HAND genes show that both of these genes are essential for proper cardiac development. Recently, we have shown that HAND1 and HAND2 exhibit promiscuous dimerization characteristics allowing for the formation of HAND homo and heterodimers as well as heterodimers with both class A and class B bHLH proteins. From our recent efforts, we are in a unique position to focus this proposal on understanding the mechanism of how HAND proteins choose their bHLH partners and which HAND dimers are required for implementing the cardiac transcriptional program. Specifically, we will define the residues that are post translationally modified in cardiac expressed bHLH factors. We will investigate the mechanism of HAND protein dimerization and how the identified protein modifications affect dimerization. Finally, we will define the role of these posttranslational modifications in cardiac-specific transcriptional regulation. The completion of this study will result in the identification of the relevant bHLH complexes mediating cardiogensis and an increased understanding of the molecular controls that drive bHLH dimerization choices. Taken together, the results of these experiments will provide a comprehensive picture of the function and regulation of the bHLH factors in the heart. This information will increase the understanding of how the molecular pathways that control cardiogenesis are organized, thereby providing a greater understanding of the molecular mechanisms controlling heart formation. This understanding is essential for the development of genetic screens and treatments for the many forms of congenital heart disease present in the human population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Schramm, Charlene A
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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VanDusen, Nathan J; Firulli, Anthony B (2012) Twist factor regulation of non-cardiomyocyte cell lineages in the developing heart. Differentiation 84:79-88
Vincentz, Joshua W; Rubart, Michael; Firulli, Anthony B (2012) Ontogeny of cardiac sympathetic innervation and its implications for cardiac disease. Pediatr Cardiol 33:923-8
Pham, Duy; Vincentz, Joshua W; Firulli, Anthony B et al. (2012) Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function. J Immunol 189:832-40
Vincentz, Joshua W; VanDusen, Nathan J; Fleming, Andrew B et al. (2012) A Phox2- and Hand2-dependent Hand1 cis-regulatory element reveals a unique gene dosage requirement for Hand2 during sympathetic neurogenesis. J Neurosci 32:2110-20
Barnes, Ralston M; Firulli, Beth A; VanDusen, Nathan J et al. (2011) Hand2 loss-of-function in Hand1-expressing cells reveals distinct roles in epicardial and coronary vessel development. Circ Res 108:940-9
Zook, Erin C; Krishack, Paulette A; Zhang, Shubin et al. (2011) Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118:5723-31
Vincentz, Joshua W; Barnes, Ralston M; Firulli, Anthony B (2011) Hand factors as regulators of cardiac morphogenesis and implications for congenital heart defects. Birth Defects Res A Clin Mol Teratol 91:485-94
Firulli, Beth A; McConville, David P; Byers 3rd, James S et al. (2010) Analysis of a Hand1 hypomorphic allele reveals a critical threshold for embryonic viability. Dev Dyn 239:2748-60
Barnes, Ralston M; Firulli, Beth A; Conway, Simon J et al. (2010) Analysis of the Hand1 cell lineage reveals novel contributions to cardiovascular, neural crest, extra-embryonic, and lateral mesoderm derivatives. Dev Dyn 239:3086-97
Barnes, Ralston M; Firulli, Anthony B (2009) A twist of insight - the role of Twist-family bHLH factors in development. Int J Dev Biol 53:909-24

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