Hyaluronan (HA) and proteoglycans (PGs) are major extracellular matrix (ECM) components in the developing endocardial cushions of the heart. They have been demonstrated to play an important role in regulation of endocardial-to-mesenchymal transformation. We have recently determined that Cartilage link protein 1 (Crtl1) is expressed in the heart as well. Crtl1 mediates the binding of HA to PGs and is best known for its role in stabilizing the hyaluronan/aggrecan complex in cartilage. In the mouse heart, Crtl1 expression was found in the endocardium and in the endocardially-derived atrioventricular (AV) cushions where it is, not surprisingly, largely co-localized with versican and HA. Thorough analysis of the cardiac phenotype of the Crtl1 knock out mouse demonstrates that, at early stages, Crtl1-/- animals are characterized by a spectrum of cardiac abnormalities, including thin myocardial walls and under-developed ventricular septa. Late fetal and neonatal mutant mice display a spectrum of valvuloseptal abnormalities, including muscular ventricular and atrioventricular septal defects. From our observations, we infer that Crtl1 is an important component in the extracellular matrix of the developing heart where it plays a significant role in the development of myocardial structures and endocardial cushion tissues.
In specific aim 1 we plan to determine the role of endocardially-expressed Crtl1 in early stages of cardiac development. Specifically, we will test the hypothesis that, as a result of the absence of Crtl1, the balance between myocardial proliferation and apoptosis is disturbed.
In aim 2 we have designed experiments to determine how Crtl1, in combination with its binding partners hyaluronan and versican, is involved in regulation of early myocardial development. Finally, in aim 3 we will investigate whether Crtl1 plays a role in EMT and/or in the regulation of post-EMT events in the endocardial cushions of the developing heart. Relevance of project: Each year, nearly twice as many children die in the US from congenital heart disease as die from all forms of childhood cancers combined. Almost all abnormalities found in CHD involve the valvuloseptal complex. Understanding the role of Crtl1, and Crtl1-associated mechanisms, in heart development may further our knowledge of the etiology of a variety of these malformations including the mechanisms that lead to muscular septal defects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084285-04
Application #
7744017
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2007-01-01
Project End
2012-06-30
Budget Start
2010-01-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$365,000
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
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Briggs, Laura E; Kakarla, Jayant; Wessels, Andy (2012) The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation 84:117-30
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Wirrig, Elaine E; Snarr, Brian S; Chintalapudi, Mastan R et al. (2007) Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development. Dev Biol 310:291-303

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