Hedgehog signaling controls gene regulatory networks for early cardiovasculogenesis

Doctor's Name: 
Alexander Guzzetta
Hospital/Institution: 
University of Chicago

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

(Total Grant Amount $51,900; CHF portion = $28,026)

The heart is a remarkably complex organ that undergoes radical and frequent changes during its development. Congenital heart disease (CHD), results from improper heart development is present in 3 of 100 births. Although we currently understand that there is a strong heritable component to these disorders, the genetic basis for CHD is mostly unsolved. In this study, we investigate a genetic network controlled by the hedgehog signaling pathway responsible for the initial construction of the cardiovascular system. Upon removal of hedgehog activity, we observe embryonic lethality due to improper cardiac formation. Understanding the suite of genes directed by hedgehog in this process is crucial towards the understanding of the genetic and mechanistic basis of many forms of human CHD.

The main goal of this study is to understand how genes coordinately build the earliest components of the heart. Due to the power of mouse genetics, we can disrupt genes critical to heart development and gain understanding and make predictions about how these individual elements work together in the larger fabric of heart development. We can then experimentally test the manner in which these genes work together and function using a combination of molecular biology and genetic approaches. Due to our adoption of recent cutting edge tools, we can apply this experimental logic to a historically challenging window of development at the earliest stages of heart development in the context of altered hedgehog signaling. This allows us to find new genes that potentially contribute to CHD.

As a means to contribute to the AHAs chief goal of reducing cardiovascular disease, our primary focus in this study is to uncover the core genetic components of early cardiovascular development. Genes identified from this study can be used as candidates in subsequent human studies to validate the genetic drivers of human CHD. Although we can correct many of these defects surgically, understanding the genetic diagnosis in each individual patient is essential to their life-long treatment and prevention of continued morbidity. We believe that this study will yield foundational mechanistic insights towards new diagnostic measures and personalized medicine for patients living with CHDs.

Award Date 1: 
2017
Award Amount 1: 
$28,026