Cardiac endocardial cushion morphogenesis in the atrioventricular (AV) canal requires an epithelial-tomesenchymal cell transition (EMT) to form a population of cells that contribute to valve leaflet formation and cardiac septation. Abnormal AV canal development can result in a common, severe form of congenital heart disease, and computer modeling predicts these defects can result from altered cell adhesiveness. While considerable progress has been made in understanding how multiple families of growth factors regulate EMT, far less is known about how the interaction of cells with the surrounding ECM influences EMT. One important class of transmembrane receptors that link the ECM with intracellular signaling pathways is the integrin family of cell surface receptors. Although early studies demonstrated that an interaction of beta1 integrins with the ECM is required for AV canal EMT, almost nothing is known about which integrin heterodimers are involved or how they contribute to this important developmental event. We have found that cells from infants with heart valve defects display altered adhesion on collagen type VI, a component of the developing heart valve ECM. Importantly, we identified alpha 3 beta 1 integrin as the receptor mediating this process, and preliminary studies from our laboratory implicate an important role for this specific integrin receptor during AV canal EMT. These data lead to the central hypothesis that alpha 3 beta 1 integrin is required for AV canal development by forming a structural link to specific ECM ligands that necessary for cell migration, and by directing gene expression during EMT through beta 1 integrin-mediated intracellular signaling. This hypothesis will be tested by experiments that will determine alpha 3 integrin's role during AV canal EMT and define the beta 1 integrin-mediated signaling pathways that are required during heart valve development. These studies will contribute to our fundamental knowledge of the role of integrins in heart valve development and EMT. From a clinical perspective, this research is significant because 10% of all infants with heart defects are directly attributed to improper AV valve development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074070-03
Application #
7017745
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Schramm, Charlene A
Project Start
2004-04-01
Project End
2008-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$348,949
Indirect Cost
Name
University of Arizona
Department
Pediatrics
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Klewer, Scott E; Yatskievych, Tatiana; Pogreba, Kristen et al. (2006) Has2 expression in heart forming regions is independent of BMP signaling. Gene Expr Patterns 6:462-70