Normal heart morphogenesis requires the controlled migration of several populations of cells including endocardial cushion mesenchymal cells, epicardial cells and cells of neural crest origin. Fibulin-1 is an extracellular matrix (ECM) protein, whose expression coincides spatially and temporally with growth and migratory events occurring in the endocardial cushions and epicardium as well as other sites of epithelial- mesenchymal transformation including neural crest. Our recent findings indicate that fibulin-1 is a potent inhibitor of cells motility promoted fibronectin, including that of cardiac cushion mesenchymal cells in vitro. A novel hypothesis that will be addressed by experiments proposed in this application is that fibulin-1 functions to regulate morphogenic cell movements in the developing heart by suppressing the motility-promoting activity of fibronectin and perhaps other ECM components of the endocardial cushion, myocardium and epicardium. The first part of the study will focus on characterizing the effects of fibulin-1 on mortality of the major cell types involved with valvuloseptal morphogenesis using in vitro assays that measure motility and haptotactic migration of the endocardial, myocardial, epicardial and neural crest cells. The second part of the study will evaluate the consequence of heart morphogenesis of experimental in vivo modulation of fibulin-1 expression in the epicardium, myocardium and endocardium. This will involve embryonic heart microinjection of fibulin-1 and fibulin-1 antibodies as well as transgenic approaches designed to augment fibulin-1 expression in specific embryonic heart tissues. The transgenic approaches will include heart injection of fibulin 1-expressing adenovirus and tissue-specific expression of fibulin-1 under the control of endocardial and myocardial- specific gene promoters. The third part of the study will explore the underlying mechanisms for the suppressive effects of fibulin-1 on cell motility by identifying the cell surface receptor(s) that mediates its effect on cell motility and mapping the region(s) within fibulin 1 responsible for suppressing cell motility. Experiments proposed in this later aim will also seek to characterize the major intracellular signaling pathways that fibulin-1 modulates with emphasis on the regulation of the actomyosin complex.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL052813-07
Application #
6410540
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2001-01-01
Project End
2001-12-31
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
$194,477
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Moreno-Rodriguez, Ricardo A; Krug, Edward L; Reyes, Leticia et al. (2017) Linear array of multi-substrate tracts for simultaneous assessment of cell adhesion, migration, and differentiation. Biotechniques 63:267-274
Fresco, Victor M; Kern, Christine B; Mohammadi, Moosa et al. (2016) Fibulin-1 Binds to Fibroblast Growth Factor 8 with High Affinity: EFFECTS ON EMBRYO SURVIVAL. J Biol Chem 291:18730-9
Twal, Waleed O; Hammad, Samar M; Guffy, Sharon L et al. (2015) A novel intracellular fibulin-1D variant binds to the cytoplasmic domain of integrin beta 1 subunit. Matrix Biol 43:97-108
Zyblewski, Sinai C; Argraves, W Scott; Graham, Eric M et al. (2012) Reduction in postoperative high-density lipoprotein cholesterol levels in children undergoing the Fontan operation. Pediatr Cardiol 33:1154-9
Argraves, Kelley M; Sethi, Amar A; Gazzolo, Patrick J et al. (2011) S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. Lipids Health Dis 10:70
Snarr, Brian S; Kern, Christine B; Wessels, Andy (2008) Origin and fate of cardiac mesenchyme. Dev Dyn 237:2804-19
Argraves, Kelley M; Gazzolo, Patrick J; Groh, Eric M et al. (2008) High density lipoprotein-associated sphingosine 1-phosphate promotes endothelial barrier function. J Biol Chem 283:25074-81
Cooley, Marion A; Kern, Christine B; Fresco, Victor M et al. (2008) Fibulin-1 is required for morphogenesis of neural crest-derived structures. Dev Biol 319:336-45
Okagawa, Hiroto; Markwald, Roger R; Sugi, Yukiko (2007) Functional BMP receptor in endocardial cells is required in atrioventricular cushion mesenchymal cell formation in chick. Dev Biol 306:179-92
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

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