Our observations of the heart defect (hdf) null embryo has provided remarkable evidence that the Cspg2 gene (versican) has an unexpectedly important role in the growth and differentiation of the outlet segment (conotruncus) of the heart. We propose to determine the critical role of versican in a region that is a """"""""hot spot"""""""" for clinically important birth defects affecting over one-half of all human live birth heart defects. The conotruncus of the developing outlet forms from a previously unrecognized mesodermal heart field located anteriorly to the primitive ventricle. We propose the Cspg2 gene promotes differentiation and stabilization of the myocardial phenotype as a contractile and inductive signaling tissue in the growing conotruncus. Our hypothesis is that 1) specific functional domains of Cspg2 are required for normal myocardial recruitment in the growing outlet and 2) the programmed loss of the truncus myocardium during the late remodeling stages results from the absence of specific functional domains of Cspg2. An abnormal loss or other variation of versican expression at the early recruitment or later remodeling stages, affects the normal patterns of phenotypic stabilization in the truncus myocardium and results in conotruncal heart defects. We propose the following Specific Aims: 1) To determine the expression patterns of Cspg2 functional domains in the developing conotruncus during (a) early recruitment of the myocardium from the anterior heart field mesoderm (AHF) and during (b) later stages when the truncal myocardium is known to regress; 2) To test the hypothesis that Cspg2 functions to stabilize the conotruncus phenotype by overexpressing Cspg2 in a whole animal transgenic mouse model.; 3) To determine if specific Cspg2 functional domains are required for recruitment and/or stabilization of the conotruncus myocardium's contractile and inductive signalling phenotypes; 4) To determine if specific domains of the Cspg2 protein have a functional role later in contruncal development to remodel the truncus by destabilizing the myocardium for transdifferentiation into a fibrous connective tissue.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066231-04
Application #
6749033
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Schramm, Charlene A
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$286,000
Indirect Cost
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Shivshankar, Pooja; Halade, Ganesh V; Calhoun, Cheresa et al. (2014) Caveolin-1 deletion exacerbates cardiac interstitial fibrosis by promoting M2 macrophage activation in mice after myocardial infarction. J Mol Cell Cardiol 76:84-93
Hudson, Karla S; Andrews, Kristen; Early, June et al. (2010) Versican G1 domain and V3 isoform overexpression results in increased chondrogenesis in the developing chick limb in ovo. Anat Rec (Hoboken) 293:1669-78
Williams, Austin D; Mjaatvedt, Corey H; Moore, Clara S (2008) Characterization of the cardiac phenotype in neonatal Ts65Dn mice. Dev Dyn 237:426-35
Norris, Russell A; Damon, Brook; Mironov, Vladimir et al. (2007) Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem 101:695-711
Kern, Christine B; Norris, Russell A; Thompson, Robert P et al. (2007) Versican proteolysis mediates myocardial regression during outflow tract development. Dev Dyn 236:671-83
Butcher, Jonathan T; Norris, Russell A; Hoffman, Stanley et al. (2007) Periostin promotes atrioventricular mesenchyme matrix invasion and remodeling mediated by integrin signaling through Rho/PI 3-kinase. Dev Biol 302:256-66
Moreno-Rodriguez, R A; Krug, E L; Reyes, L et al. (2006) Bidirectional fusion of the heart-forming fields in the developing chick embryo. Dev Dyn 235:191-202
Kern, Christine B; Twal, Waleed O; Mjaatvedt, Corey H et al. (2006) Proteolytic cleavage of versican during cardiac cushion morphogenesis. Dev Dyn 235:2238-47
Mjaatvedt, Corey H; Kern, Christine B; Norris, Russel A et al. (2005) Normal distribution of melanocytes in the mouse heart. Anat Rec A Discov Mol Cell Evol Biol 285:748-57
Norris, Russell A; Kern, Christine B; Wessels, Andy et al. (2005) Detection of betaig-H3, a TGFbeta induced gene, during cardiac development and its complementary pattern with periostin. Anat Embryol (Berl) 210:13-23

Showing the most recent 10 out of 13 publications