Cardiovascular anomalies represent one of the most prevalent congenital birth defects observed. Of these anomalies, a significant proportion manifest as an alteration in the formation of structures derived from the development of the atrioventricular (AV) canal. We have identified the Jak-STAT signal transduction pathway as playing a role in regulating the formation of the AV canal. Our data show that numerous members of the Jak-STAT pathway are localized to the AV canal, and that by blocking the function of Jak3 we can inhibit normal AV canal formation. This proposal seeks to gain insight into the molecular interactions that regulate this pathway in the AV canal by: (1) determining which STAT members of the pathway are active in the AV canal; and (2) identifying the upstream activators of the pathway and their site(s) of action in regulating the morphogenesis of the AV canal. By exploiting the use of 3-dimensional collagen gel bioassay and recent gene targeting techniques, such as antisense oligonucleotides, morpholinos, RNAi and function-perturbing chemical modulators, to inhibit specific Jak and STAT molecules we intend to test the following hypothesis: that activation of the Jak-STAT pathway controls proper AV canal formation and is reflected in the expression of key markers of the transformation process. Our tenets will be tested in the following aims.
Aim 1 : Characterize the specific STAT members of the pathway activated in epithelial to mesenchymal cell transformation (EMT) that occurs during AV canal morphogenesis.
Aim 2 : Establish the precise tissue in which the Jak-STAT pathway is functioning in regulation of the EMT process, i.e. myocardium or endothelium.
Aim3 : Identify the upstream activators of Jak3 that function through the IL-2R pathway. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL072958-01A1
Application #
6720958
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Schramm, Charlene A
Project Start
2004-03-01
Project End
2008-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$310,644
Indirect Cost
Name
University of South Carolina at Columbia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
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