Mutational Analysis of TGF beta Function. Congenital heart disease occurs in nearly 1 percent of all live births in the United States. Over 1/3 of these involve ventral and atrial septal defects and outflow tract defects. About a quarter of all heart defects result in critical disease, and even with modern medical practices about 1/3 of these still do not support life past one year. Even though congenital heart defects have both environmental as well as genetic components, genetic models of these abnormalities will be useful for identifying the molecular pathways through which both environmental and genetic factors can interfere. Therefore, identification of these pathways will likely lead to improved diagnostic, intervention and treatment strategies that will be applicable to both the environmental and genetic components of congenital heart disease. Transforming Growth Factor beta 2 (TGFbeta2) knockout mice have congenital heart abnormalities that are commonly found in humans: double outlet right ventricle, double inlet left ventricle, ventral and atrial septal defects, and valve defects. For the 4-chambered heart to form with proper alignment of the great vessels with their respective ventricles, considerable morphogenesis and remodeling must occur. Defects in either cushion formation or the subsequent myocardialization of those cushions could lead to such congenital abnormalities. We propose an in depth analysis of 1) the process of cushion formation, in which an epithelial- mesenchymal transformation of the endocardial cells into cushion mesenchyme occurs, and 2) the process of myocardialization, in which inner curvature myocardial cells, with the help of neural crest cells, invade and muscularize the cushion mesenchyme. We will apply immunohistochemical, in situ hybridization and electron mircroscopy techniques to normal and knockout embryonic hearts to analyze alterations in expression of the cell adhesion, migration, extracellular matrix and differentiation molecules that may be involved in these processes. We will also determine which cells are responsible for producing the TGFbeta2 needed for these processes to occur normally by transgenic rescue and conditional knockout, both in myocardial and neural crest cells. Finally, we will use functional genomics to discover new candidate genes involved in these essential processes of heart development. With this study we will obtain a much better understanding of the molecular mechanisms underlying the most common congenital heart abnormalities in man.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD026471-13
Application #
6619492
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Moody, Sally Ann
Project Start
1990-05-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
13
Fiscal Year
2003
Total Cost
$375,184
Indirect Cost
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Daniel, Scott G; Ball, Corbie L; Besselsen, David G et al. (2017) Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor ?-Deficient Colon Cancer. mSystems 2:
Doetschman, Thomas (2011) GI GEMs: genetically engineered mouse models of gastrointestinal disease. Gastroenterology 140:380-385.e2
House, Stacey L; House, Brian E; Glascock, Betty et al. (2010) Fibroblast Growth Factor 2 Mediates Isoproterenol-induced Cardiac Hypertrophy through Activation of the Extracellular Regulated Kinase. Mol Cell Pharmacol 2:143-154
Liao, Siyun; Bodmer, Janet R; Azhar, Mohamad et al. (2010) The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury. J Mol Cell Cardiol 48:1245-54
Azhar, Mohamad; Runyan, Raymond B; Gard, Connie et al. (2009) Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development. Dev Dyn 238:431-42
Doetschman, Thomas (2009) Influence of genetic background on genetically engineered mouse phenotypes. Methods Mol Biol 530:423-33
Saxena, Vijay; Lienesch, Douglas W; Zhou, Min et al. (2008) Dual roles of immunoregulatory cytokine TGF-beta in the pathogenesis of autoimmunity-mediated organ damage. J Immunol 180:1903-12
Bommireddy, Ramireddy; Babcock, George F; Singh, Ram R et al. (2008) TGFbeta1 deficiency does not affect the generation and maintenance of CD4+CD25+FOXP3+ putative Treg cells, but causes their numerical inadequacy and loss of regulatory function. Clin Immunol 127:206-13
Bommireddy, Ramireddy; Doetschman, Thomas (2007) TGFbeta1 and Treg cells: alliance for tolerance. Trends Mol Med 13:492-501
Bommireddy, Ramireddy; Pathak, Leena J; Martin, Jennifer et al. (2006) Self-antigen recognition by TGF beta1-deficient T cells causes their activation and systemic inflammation. Lab Invest 86:1008-19

Showing the most recent 10 out of 36 publications