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Congenital Heart Disease: In Search of Remedial Etiologies.


Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology [Internet]. Tokyo: Springer; 2016. Chapter 5.
2016 Jun 25.

Author information

Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Cardiovascular Developmental Biology Center, Medical University of South Carolina Clemson University, Charleston, South Carolina, USA
Department of Pediatrics (Cardiology), Vanderbilt University, Nashville, Tennessee, USA
Pediatrics, Pharmacology and Toxicology, and Bioengineering, University of Louisville, Louisville, Kentucky, USA
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, Japan
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Room BSB-648B, 250508, Charleston, SC, 29425, USA


In searching for remedial etiologies for congenital heart disease (CHD), we have focused on identifying interactive signaling pathways or “hubs” in which mutations disrupt fundamental cell biological functions in cardiac progenitor cells in a lineage-specific manner. Based on the frequency of heart defects seen in a clinical setting, we emphasize two signaling hubs – nodal kinases activated by extracellular ligands (e.g., periostin) and the cytoskeletal regulatory protein, filamin A (FLNA). We discuss them in the context of valve and septal development and the lineages which give origin to their progenitor cells. We also explore developmental windows that are potentially amenable to remedial therapy using homeostatic mechanisms like those revealed by a chimeric mice model, i.e., irradiated animals whose bone marrow had been reconstituted with GFP+ hematopoietic stem cells, that shows bone marrow-derived cells track to the heart, engraft, and give rise to bona fide fibroblasts. We propose to use this model to deliver genetic payloads or protein cargos during the neonatal period to override biochemical or structural deficits of CHD associated with valve and septal signaling hubs or fibroblast/myocyte interactions. Preliminary tests of the model indicate remedial potential for cardiac injuries.

Copyright 2016, The Author(s).

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