Cardiovascular malformations are estimated to cause in the US birth defects in 1 percent of children and 10 times as many stillbirths. The primary genetic defects leading to congenital cardiomyopathies are mostly not understood. However, because heart development involves a series of complex tissue movements, fusions, and remodelings, in many cases congenital cardiac abnormalities are thought to arise from defects in morphogenesis during embryonic development. Our long-term goal is to understand the transcriptional regulation of embryonic heart tube morphogenesis. An important but poorly understood process is the formation of the primitive heart tube, that is patterned, along the anterior/posterior axis, leading to programs of chamber- specific gene expression. The myocardium is derived from mesoderm, and recent molecular genetic analyses have therefore focused on the regulation and development of cardiogenic mesoderm. However, embryological and recent genetic experiments indicate that endoderm also plays an important function in regulating cardiogenesis, although the molecular and physiological basis is not known. Current data is consistent with a hypothesis that presumptive and developing foregut endoderm, regulated by GATA transcription factors downstream of retinoid signaling, is critical for proper heart tube patterning and morphogenesis. We propose to use a novel vitamin-A deficient quail model to test this hypothesis, using transplantation experiments and retroviral expression techniques. We will test the function of candidate known and novel endoderm-expressed genes, including those identified in micro-array expression experiments using differentiating GATA-4 deficient murine ES cells. It is anticipated that conserved genetic components of endoderm development will be identified with relevance to heart tube morphogenesis.
The specific aims are to: 1. Determine if retinoid signaling is required in foregut for early heart tube morphogenesis. 2. Determine if GATA factor expression is sufficient to rescue foregut development and early heart tube morphogenesis in the absence of retinoid signaling. 3. Identify GATA factor targets expressed in foregut endoderm relevant to heart tube morphogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064282-04
Application #
6629071
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Schramm, Charlene A
Project Start
2000-02-15
Project End
2004-06-30
Budget Start
2003-02-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$383,123
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071036636
City
Bronx
State
NY
Country
United States
Zip Code
10461
Sedletcaia, Anya; Evans, Todd (2011) Heart chamber size in zebrafish is regulated redundantly by duplicated tbx2 genes. Dev Dyn 240:1548-57
Kikuchi, Kazu; Holdway, Jennifer E; Werdich, Andreas A et al. (2010) Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464:601-5
Choudhuri, Avik; Evans, Todd; Maitra, Umadas (2010) Non-core subunit eIF3h of translation initiation factor eIF3 regulates zebrafish embryonic development. Dev Dyn 239:1632-44
Holtzinger, Audrey; Rosenfeld, Gabriel E; Evans, Todd (2010) Gata4 directs development of cardiac-inducing endoderm from ES cells. Dev Biol 337:63-73
Das, Bhaskar C; Mahalingam, Sakkarapalayam M; Panda, Lipsa et al. (2010) Design and Synthesis of Potential New Apoptosis Agents: Hybrid Compounds Containing Perillyl Alcohol and New Constrained Retinoids. Tetrahedron Lett 51:1462-1466
Rikin, Amir; Evans, Todd (2010) The tbx/bHLH transcription factor mga regulates gata4 and organogenesis. Dev Dyn 239:535-47
Rikin, Amir; Rosenfeld, Gabriel E; McCartin, Kellie et al. (2010) A reverse genetic approach to test functional redundancy during embryogenesis. J Vis Exp :
Das, Bhaskar C; McCartin, Kellie; Liu, Ting-Chun et al. (2010) A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity. PLoS One 5:e10004
Torregroza, Ingrid; Evans, Todd; Das, Bhaskar C (2009) A forward chemical screen using zebrafish embryos with novel 2-substituted 2H-chromene derivatives. Chem Biol Drug Des 73:339-45
Das, Bhaskar C; Mahalingam, Sakkarapalayam M; Evans, Todd (2009) Design and synthesis of novel pinacolylboronate containing combretastatin 'antimitotic agent' analogues. Tetrahedron Lett 50:3031-3034

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