Intercellular communication plays diverse roles in the embryological and postnatal development of the heart. Correspondingly, insight into developmental mechanisms governing the organization of cell-cell coupling may significantly inform the origins of electrophysiological instabilities in the diseased heart. The disorganized patterns of cell coupling common to various pathologies of the myocardium, re-capitulate patterns of gap junction (gj) distribution found in differentiating myocardium. As detailed herein, we have made significant progress in understanding patterning of gjs in the developing heart - also laying a foundation for renewal of this project. In particular, we have developed strong evidence for a novel potential function of a connexin interacting protein, ZO-1, in gj remodeling. Our specific hypothesis is that a ZO-1 basedmechanism has a role in a gj endocytosis process that may impact developmental remodeling of electrical coupling patterns between myocytes. In addition, we have derived evidence for a role for coronary arteriogenesis in determining gj distribution and connexin expression in studies of a transgenic model of sudden cardiac death (the HF1b knockout mouse). To build on these observations we aim to; 1) use membrane translocating peptides and adenoviral vectors to target ZO-1-Cx43 interactions, investigating the role of ZO-l in Cx43 gj remodeling in Langendorff perfused heart and cell culture preparations ; 2) use fluorescent ZO-1 and Cx43 fusion proteins, and stably transfected cell lines, to directly observed ZO-I-Cx43 interactions and Cx43 gj function in vivo ; 3) use adenoviral vectors and inhibitory peptides targeting ZO-l-Cx43 interactions to investigate the role of ZO-1 in Cx43 gj patterning in cardiac development and disease; and ; 4) characterize whether loss of ZO-I function and/or abnormalities in coronary arteriogenesis have a role in defective gj patterning in the working myocardium and ventricular conduction tissues of the HF lb knockout mouse heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056728-09
Application #
6900266
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Wang, Lan-Hsiang
Project Start
1997-07-01
Project End
2006-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
9
Fiscal Year
2005
Total Cost
$255,500
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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