Congenital Heart Disease: In Search of Remedial Etiologies

Excerpt

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.