The long term goal of this project is to further the understanding of the molecular mechanism of cardiac development end the pathogenesis of congenital heart disease, particularly that of the tetralogy of Fallot (TOF), through the study of the cardiac transcription factor Nkx2.5 (Csx). NKX2.5 is the only gene, so far, reported in humans whose mutations accounts for a significant portion (4-5%) of patients with non-syndromic sporadic TOF. Nkx2.5 is among the first genes to be expressed in the precardiac mesoderm. Homozygous deletion of Nkx2.5 causes early embryonic lethality due to cardiac outflow tract obstruction, ventricular dysfunction and the arrest of chamber formation. The continued expression of the Nkx2.5 in the heart throughout development into the adult stage suggests that target genes for Nkx2.5 protein may also be important to the maintenance of cardiac function postnatally. Indeed our preliminary results indicate that Nkx2.5 heterozygous mice display a distinct genetic response to myopathic stress and are much more susceptible to arrhythmias and heart failure. Our preliminary results also suggest that Nkx2.5 have different target genes at different stages of development and different regions of the heart. In addition, Nkx2.5 is known to interact directly with other important cardiac transcription factors, such as Tbx5, GATA4 and SRF. These results suggest that further studies of the Nkx2.5 gene function are likely to yield many important new insights into the pathogenesis of congenital heart disease, particularly that of TOF in humans. Accordingly, we will address the following Specific Aims in this proposal:
Specific Aim 1 : To identify the mechanism of an increased susceptibility to heart failure in Nkx2.5 heterozygous mutant mice.
Specific Aim 2 : To create mouse models of TOF by targeted mutations in Nkx2.5 in the identical positions found in patients, and, if necessary, crossing with other mutant mice that have a conotruncal phenotype.
Specific Aim 3 : To perform transcriptional profiling of RV biopsies of patients with TOF to compare the pattern of gene expression in the mouse model and humans.
Specific Aim 4 : To identify targets of Nkx2.5 in the developing outflow truct, whose alterations can cause conotruncal abnormalities.
Specific Aim 5 : To identify Nkx 2.5 associated proteins by proteomics approach and study how protein - protein interactions provide specificity to target gene regulation by Nkx2.5 protein.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL074734-05
Application #
7576839
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$730,603
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Tang, Dalin; Zuo, Heng; Yang, Chun et al. (2017) Comparison of Right Ventricle Morphological and Mechanical Characteristics for Healthy and Patients with Tetralogy of Fallot: An In Vivo MRI-Based Modeling Study. Mol Cell Biomech 14:137-151
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He, Huamei; Tao, Hai; Xiong, Hui et al. (2014) Rosiglitazone causes cardiotoxicity via peroxisome proliferator-activated receptor ?-independent mitochondrial oxidative stress in mouse hearts. Toxicol Sci 138:468-81
Tang, Dalin; Yang, Chun; Geva, Tal et al. (2013) A Multiphysics Modeling Approach to Develop Right Ventricle Pulmonary Valve Replacement Surgical Procedures with a Contracting Band to Improve Ventricle Ejection Fraction. Comput Struct 122:78-87

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