description): The transition of the embryonic heart from a single to a dual circulation requires remodeling of the cardiac outflow tract (OFT). This remodeling involves shortening and rotation of the myocardial portion of the OFT, and division of the single lumen by septation. These processes result in a heart in which the pulmonary artery (PA) connects to the right ventricle (RV) and to the right of the aorta that connects directly to the left ventricle. In a number of congenital human heart defects, i.e., conotruncal defects, there is a misalignment of the myocardial infundibulum with the great vessels. The lab has shown using a recombinant adenovirus (CMV promoter) that shortening of the OFT occurred between ED5-8 during chick development with the OFT myocardium comprising the infundibular connection of the RV to the PA. Concomitant with OFT shortening was a high incidence of apoptosis of the OFT cardiomyocytes, and activation of the caspase cascade. The hypothesis is that OFT myocyte apoptosis is necessary for OFT shortening and rotation, and that perturbations of OFT myocyte apoptosis will result in defects in the ventriculo-arterial connections modeling human conotruncal defects.
Aims i nclude 1) targeting inhibitors of apoptosis to the OFT myocardium with the adenovirus; 2) precociously activating apoptosis in the OFT myocardium via the fas receptor; and 3) examining the molecular pathway responsible for the tightly regulated apoptosis of the OFT cardiomyocytes, specifically the BMP-mediated pathway.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065314-02
Application #
6390825
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Wang, Lan-Hsiang
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$306,000
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kenchegowda, Doreswamy; Natale, Bryony; Lemus, Maria A et al. (2017) Inactivation of maternal Hif-1? at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress. Dev Biol 422:171-185
Wang, Fang; Fisher, Steven A; Zhong, Jianxiang et al. (2015) Superoxide Dismutase 1 In Vivo Ameliorates Maternal Diabetes Mellitus-Induced Apoptosis and Heart Defects Through Restoration of Impaired Wnt Signaling. Circ Cardiovasc Genet 8:665-76
Yang, Peixin; Kenchegowda, Doreswamy; Fisher, Steven A (2014) Cardiac myocyte proliferation: not as simple as counting sheep. J Mol Cell Cardiol 74:125-6
Kenchegowda, Doreswamy; Liu, Hongbin; Thompson, Keyata et al. (2014) Vulnerability of the developing heart to oxygen deprivation as a cause of congenital heart defects. J Am Heart Assoc 3:e000841
Outeda, Patricia; Huso, David L; Fisher, Steven A et al. (2014) Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep 7:634-44
Wikenheiser, Jamie; Karunamuni, Ganga; Sloter, Eddie et al. (2013) Altering HIF-1? through 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure affects coronary vessel development. Cardiovasc Toxicol 13:161-7
Karunamuni, Ganga; Yang, Ke; Doughman, Yong Qiu et al. (2010) Expression of lymphatic markers during avian and mouse cardiogenesis. Anat Rec (Hoboken) 293:259-70
Yang, Ke; Doughman, Yong-Qiu; Karunamuni, Ganga et al. (2009) Expression of active Notch1 in avian coronary development. Dev Dyn 238:162-70
Vickerman, Mary B; Keith, Patricia A; McKay, Terri L et al. (2009) VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken) 292:320-32
Wikenheiser, Jamie; Wolfram, Julie A; Gargesha, Madhusudhana et al. (2009) Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn 238:2688-700

Showing the most recent 10 out of 24 publications