Cellular and Molecular Mechanisms of Left Ventricular Growth and Morphogenesis

Project: Research project

Project Details

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 (OMIM# 605067), Pulmonary Atresia (OMIM# 265150), and Hypoplastic Left Heart Syndrome
(HLHS; 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.
Human mutations in the cardiac transcription factor genes NKX2.5 and HAND1 have been observed in HLHS
patients. Modeling and thus the study of possible HLHS phenotypes have been limited as current systemic and
conditional knockouts of Nkx2.5 and Hand1 results in embryonic lethality given the broad expression domains
of available Cre lines. The lack of a restricted left ventricle Cre driver prohibits such investigations. Hand1 is
expressed within the primary heart field myocardium of the left ventricle. We have isolated the enhancer that
regulates Hand1 left ventricular expression and used it to generate a novel left ventricular-specific Cre driver
with which interrogation of the cellular and molecular mechanism driving left ventricular morphogenesis can be
realized. Our experimental plan is to ablate the Hand1 left ventricular lineage cells from the developing
embryonic heart, conditionally delete Nkx2.5 specifically within the left ventricular myocardium, and validate an
identified human mutation in HAND1 isolated from 24 unrelated patients as being causative of HLHS. This
study of the role that Hand1-lineage myocardium plays during cardiogenesis will shed light on the cell etiology
of single ventricle phenotypes and on the molecular programs controlling ventricular maturation, thus
expanding the understanding of ventricular morphogenesis as it relates to human disease.
Relevance:
CHDs resulting in single ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an
understanding of the etiology and molecular mechanisms that cause CHDs resulting in a single ventricle heart
has the potential to benefit thousands of pediatric patients annually. The Hand1-lineage plays a key role in the
genesis of single ventricle phenotypes and gaining insight into the cellular and molecular mechanism of this
understudied myocardial population will have a great benefit to developing non-surgical treatments for CHD
patients.
StatusFinished
Effective start/end date12/15/1311/30/17

Funding

  • National Institutes of Health: $384,150.00
  • National Institutes of Health: $390,000.00
  • National Institutes of Health: $390,000.00

ASJC

  • Medicine(all)

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