Endocardial mechanisms of cardiac trabeculation and septation

Project: Research project

Description

PROJECT SUMMARY/ABSTRACT
Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle
phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses and include
Tricuspid Atresia (TA; OMIM# 605067), Double Inlet Left Ventricle (DILV), Pulmonary Atresia (OMIM# 265150),
and Hypoplastic Left Heart Syndrome (OMIM# 241550, 614435). The single ventricle heart presents with a
series circuit such that systemic venous return to the right ventricle and pulmonary arteries combined with the
flow from the pulmonary venous return into the left ventricle and out to the body is incompatible with survival.
Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the
many forms of single ventricle CHD.
The Basic helix-loop-helix factor Hand2 is expressed within the myocardium of the second heart field (SHF),
epicardium, cardiac neural crest cells, and endocardium. Hand2 deletion results in E10.5 embryonic lethality
due to the decreased growth in SHF-derived cardiac structures. Mef2c-Cre deletion of Hand2 from SHF
progenitor cells, results in TA/ DILV phenotypes. We have recently determined that the observed single
ventricle phenotypes are a direct consequence of Hand2 function in the endocardium. The function of Hand2
within the endocardium has not been investigated. Our findings lead to a novel hypothesis that signaling from
the developing endocardium is critical in determining the position of the ventricular septum, which may
potentially explain the etiology of some single ventricle CHDs. We outline a strategy to both characterize
Hand2 endocardial function, to identify the direct upstream endocardial signaling network for Hand2, and the
Hand2-downstream transcriptional targets within the developing endocardium. Defining these endocardial
signaling pathways and developmental programs regulated by Hand2 will shed light on the cell etiology of
single ventricle phenotypes and on the molecular programs controlling ventricular septation, thus expanding
the understanding of ventricular wall trabeculation, and septal morphogenesis.
StatusFinished
Effective start/end date12/15/1311/30/17

Funding

  • National Institutes of Health: $477,360.00
  • National Institutes of Health: $30,161.00
  • National Institutes of Health: $470,199.00
  • National Institutes of Health: $390,000.00

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Endocardium
Heart Ventricles
Genetic Databases
Phenotype
Morphogenesis
Heart Diseases
Hypoplastic Left Heart Syndrome
Pulmonary Atresia
Ventricular Septum
Neural Crest
Pericardium
Tricuspid Atresia
Pulmonary Artery
Myocardium
Lung
Stem Cells
Growth

ASJC

  • Medicine(all)