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.
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.
|Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui et al. (2016) Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet 25:3011-3028|
|Priest, James R; Osoegawa, Kazutoyo; Mohammed, Nebil et al. (2016) De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet 12:e1005963|
|Waldron, Lauren; Steimle, Jeffrey D; Greco, Todd M et al. (2016) The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation. Dev Cell 36:262-75|
|Hoffmann, Andrew D; Yang, Xinan Holly; Burnicka-Turek, Ozanna et al. (2014) Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet 10:e1004604|
|Xie, Linglin; Hoffmann, Andrew D; Burnicka-Turek, Ozanna et al. (2012) Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation. Dev Cell 23:280-91|
|Smemo, Scott; Campos, Luciene C; Moskowitz, Ivan P et al. (2012) Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease. Hum Mol Genet 21:3255-63|
|Kim, Eun Young; Chen, Li; Ma, Yanlin et al. (2012) Enhanced desumoylation in murine hearts by overexpressed SENP2 leads to congenital heart defects and cardiac dysfunction. J Mol Cell Cardiol 52:638-49|
|Arnolds, David E; Moskowitz, Ivan P (2011) Inducible recombination in the cardiac conduction system of minK: CreERTÂ² BAC transgenic mice. Genesis 49:878-84|
|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|
|Moskowitz, Ivan P; Wang, Jun; Peterson, Michael A et al. (2011) Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development. [corrected] Proc Natl Acad Sci U S A 108:4006-11|
Showing the most recent 10 out of 14 publications