Congenital Heart Disease (CHD), malformations of the heart present at birth, is the most common class of life-threatening birth defect. Atrioventricular Septal Defects (AVSDs) are a common and serious form of CHD in humans, comprising 5-10% of all CHD and a greater proportion of cases requiring surgical intervention. Gaining a mechanistic understanding of atrioventricular (AV) septation is an essential goal for improving clinical approaches to structural heart disease. This R01 renewal is based on a paradigm shift in the understanding of AV septation. Whereas the canonical view of AV septation was based on intracardiac events centered at the endocardial cushion, recent work demonstrated that cilia-required Sonic hedgehog (Shh) signaling in the Second Heart Field, outside of the heart proper, drives AV septation. During the last granting period, our laboratory significantly contributed towards this paradigm shift, both in the implication of cilia-based signaling (Kamp et al. 2010;Friedland- Little et al., 2011) and of Hedgehog signaling (Hoffmann et al, 2009;Xie et al, 2012). In this proposal, we harness a new understanding of AV septation to address the genetic etiology of AVSDs in humans and investigate the developmental mechanisms underlying AVSDs in more detail. We propose to (1) Perform targeted sequencing of the ciliome, Hedgehog signaling components, and cardiogenic transcription factors in a large cohort of AVSD patients;(2) analyze interactions between cilia genes, Hedgehog signaling components, and cardiogenic transcription factors in AVSDs;and (3) interrogate Hedgehog molecular networks in the cardiac progenitors that form the AV septum. The ultimate aim of the proposed work is to understand the genetic and molecular basis of AV septation. This proposal will increase understanding of the molecular ontogeny of human AVSDs. This work is an essential step towards defining the causes of human CHD and improving the natural history of patients with CHD.

Public Health Relevance

Congenital heart defects (CHD) are a leading cause of morbidity and mortality in infants, yet little is known about their etiology. Finding from the inital granting period implicated the cilia and Hedgehog signaling in Atrioventricular Septal Defects, a common form of serious CHD, in mice. This renewal tests the hypothesis that cilia and Hedgehog signaling defects cause Atrioventricular Septal Defects in humans, with implications for prevention and treatment of CHD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-P (02))
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Schramm, Charlene A
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University of Chicago
Schools of Medicine
United States
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Friedland-Little, Joshua M; Hoffmann, Andrew D; Ocbina, Polloneal Jymmiel R et al. (2011) A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet 20:3725-37
Arnolds, David E; Moskowitz, Ivan P (2011) Inducible recombination in the cardiac conduction system of minK: CreERT² BAC transgenic mice. Genesis 49:878-84
Arnolds, David E; Chu, Alison; McNally, Elizabeth M et al. (2011) The emerging genetic landscape underlying cardiac conduction system function. Birth Defects Res A Clin Mol Teratol 91:578-85
Kamp, Anna; Peterson, Michael A; Svenson, Karen L et al. (2010) Genome-wide identification of mouse congenital heart disease loci. Hum Mol Genet 19:3105-13