The long-term goal of the Program Project, Craniosynostosis Network, is to elucidate normal and abnormal craniofacial biology to ultimately improve the treatment of craniofacial disorders. Craniosynostosis (CS) and other skull abnormalities are among the most common human malformations and usually require surgical and medical intervention. Our Network will integrate the efforts of scientists with diverse expertise including anthropology, morphometry, imaging, birth defects, developmental biology, genetics, genomics, epidemiology, statistics, &system biology to explore the determinants of the fate of the relevant mesenchymal progenitor cells, and how abnormalities in the processes of osteogenesis contribute to disorders such as global skull growth abnormality, premature closure of sutures, in particular the coronal suture. We will use humans and mouse model systems to study normal development and malformations that characterize birth defects such as Apert, Crouzon, and Muenke syndromes &coronal nonsyndromic craniosynostosis. Our research design will be multidisciplinary including imaging, genomics, computational modeling &stem cell research;and evolutionary, developmental, &systems biology. Our approach will be hypothesis and discovery-driven, and we will generate and integrate a wide variety of human genomic, imaging, &laboratory data. The Network will be based at Mount Sinai Medical Center with the contact Principal Investigator (PI), Ethylin Wang Jabs, and multiple PIs, Inga Peter, Eric Schadt and Ihor Lemischka, and at Pennsylvania State University with MPIs Joan Richtsmeier, Patrick Drew, and Reuben Kraft. Our international and national collaborating institutions include: Hospital Necker-Enfants Maladies (France), University Hospital Heidelberg (Germany), and Hospital Sant Joan de Deu (Spain);Oxford University (UK), the International Craniosynostosis Consortium at University of California at Davis;New York State birth defect registry involved with the National Birth Defects Prevention Study based at Univ. of Iowa, directed by MPI Paul Romitti;New York University, Pennsylvania State Milton S. Hershey Medical Center;Boston Children's Hospital;Yale University, Univ. of Texas at Southwestern, and Johns Hopkins University. Our Advisory Committee includes experts in developmental biology, genomics, and system biology: Philippe Soriano from Mount Sinai Medical Center, James Sharpe of the Centre for Genomic Regulation, Barcelona, Spain, Alec Wilson of NIH NHGRI, &Richard Bonneau of New York University. Our proposal consists of Project I "From Skull Shape to Cell Activity in Coronal Craniosynostosis", Project II "Genomics Approaches to Coronal Nonsyndromic Craniosynostosis", &Project III "Systems Biology of Bone in Coronal Nonsyndromic Craniosynostosis";and two Cores: Administrative Core A and Molecular/Analytic Core B. The investigators, by engaging as an integrated group in the study of complex biological networks, and by utilizing innovative and state-of-the-art technologies, will foster an outstanding research environment. The Network is strongly committed to sharing &disseminating our findings to the scientific community at large.

Public Health Relevance

Craniosynostosis (CS) is a common birth defect that requires surgical treatment during the first year of life to prevent severe neurologic deficits. An international team of investigators will generate large genomic and expression datasets on mouse models and humans with CS by using state-of-the-art imaging, genetic, and developmental &systems biology approaches to quantitatively model novel pathways &networks involved in embryonic &postnatal development of CS. Quantitative and functional validations of these predictions will provide insights into the etiology &potential therapeutic targets for CS and many bone-related disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD078233-01A1
Application #
8803592
Study Section
Special Emphasis Panel (ZHD1-DRG-D (40))
Program Officer
Javois, Lorette Claire
Project Start
2014-09-26
Project End
2019-06-30
Budget Start
2014-09-26
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$1,523,621
Indirect Cost
$602,753
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Singh, Nandini; Dutka, Tara; Reeves, Roger H et al. (2016) Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn 245:114-22
Flaherty, Kevin; Singh, Nandini; Richtsmeier, Joan T (2016) Understanding craniosynostosis as a growth disorder. Wiley Interdiscip Rev Dev Biol 5:429-59
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