HAND TRANSCRIPTION FACTORS IN CARDIAC OUTFLOW TRACT DEVELOPMENT AND CONGENITAL HEART DISEASE

Doctor's Name: 
Vincentz, Joshua, PhD
Hospital/Institution: 
Indiana University

 

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

 (Total Grant Amount $308,000; CHF portion = $154,000)

The heart of an estimated 1 of every 100 newborns is affected by a potentially lethal birth defect. Of these defects, over half affect the region of the heart where blood exits the ventricles and enters the major blood vessels, called the outflow tract. The gene networks that orchestrate the development of the outflow tract are not well understood. Mutations in either of two genes that make proteins called HAND factors have been linked with cardiac birth defects. This study will thoroughly investigate how HAND factors regulate heart development in order to more broadly understand both how the outflow tract forms and what goes wrong when birth defects afflict the heart.

Mutations in either of two HAND factors are associated with cardiac birth defects. Within an individual cell, HAND factors work by turning on or off specific target genes, thereby controlling that cell¿s growth, movement, or identity. The two Hand factors are closely related, and may, in fact, target many of the same genes. Interestingly, both Hand factors are active in the developing outflow tract. Our group has generated various mouse genetic models with which to precisely study how Hand factor mutation affects outflow tract development. In addition to modeling heart defects, these mutant mice will enable us to identify target genes common to the two Hand factors. We then will assay whether reducing the amount of one Hand factor can correct the defects caused by an increase in another.

Currently, the only therapies available to correct birth defects within the heart are surgical. Both improved therapies and more sensitive methods to detect the genetic risk factors that lead to these defects require a complete understanding of the gene networks that control outflow tract development. Using the mouse models detailed in this proposal to both generate and correct outflow tract defects genetically will ultimately lead to two major therapeutic advances. First, these findings will identify novel genetic risk factors for cardiac birth defects. Second, these studies will identify genetic targets that will ultimately facilitate the development of drug therapies to correct these defects.

Award Date 1: 
2016
Award Amount 1: 
$154,000