(Overall) The overarching goal of this Program Project is to better understand the Developmental Mechanisms of Trachea-Esophageal Birth Defects (TEDs) in order to advance our knowledge of their etiology, enhance diagnosis, improve treatment, and inform strategies to generate TE tissue from human pluripotent stem cells (PSCs) that might ultimately be used for transplantation The trachea and esophagus (TE) arise from the separation of a common foregut tube during early fetal development. Defects in TE morphogenesis cause a spectrum of life-threatening TEDs that prevent proper breathing and feeding in newborns. TEDs including esophagealatresia(EA)andtrachea-esophagealfistula(TEF)arecorrectedbyinvasiveneonatalsurgeryand areoftenassociatedwithlong-termco-morbidity.TheetiologyofTEDs,whichoccurin~1:3500births,ispoorly understood. Although there is compelling evidence for a major genetic component, causative mutation are. only known in ~12% of TED cases worldwide. Moreover, even for the few cases where the genes involved havebeenidentified,suchastheHEDGEHOG(HH)andBMPsignalingpathwaygenes,howtheseregulate fetalTEmorphogenesis,andhencethestructuralbasisofTEDs,isunknown.Thelong-termgoalofthisproject is to determine the genetic and developmental mechanisms underlying TEDs in order to improve our understanding of their etiology, enhance diagnosis, improve treatment, and inform strategies to generate human tissue from pluripotent stem cells (PSCs) that might ultimately be used for transplantation. We have assembled an experienced and highly collaborative multi-disciplinary team of clinicians, geneticists, bioinformaticians,datascientists,imagingexperts,developmentalbiologistsandhumanstemcellbiologiststo tackle this problem using an innovative combination of human genetics, neonatal MRI, animal modeling in Xenopus and mouse, quantitative cell biology, genome editing and human PSCs derived esophageal organoids.ThiswillbeaMulti-PIprojectcenteredatCincinnatiChildren?sHospitalMedicalCenter(CCHMC)in collaboration with Columbia University Medical Center. The Multi-PIs will be: Aaron Zorn PhD (contact PI;? CCHMC), Paul Kingma MD PhD (CCHMC), James Wells PhD (CCHMC) and Wendy Chung MD PhD (Columbia). These combined expertise and resources creates a synergistic program not found at any single institution.Wepropose3innovativeandhighlysynergisticprojectsandaGenomicsCoretorevealthegenetic, molecularandcellularbasisofTED Project-1:ComprehensivephenotypicandgeneticassessmentofTEDpatients. Project-2:ModelingthemolecularandcellularmechanismsofTEDsinanimals. Project-3:ModelingTEbirthdefectsinhumanpluripotentstemcell(PSC)-derivedfetaltissues. IntegratedGenomicsCoreandAdministrativeCore

Public Health Relevance

(Overall) Thetracheaandesophagusarisefromtheseparationofacommonforeguttubeduringearlyfetal development.Defectsinthisprocesscausetracheo-esophagealBirthDefects;?aspectrumoflife-threatening congenitaldisorders,occurin~1:3500births,thatpreventproperbreathingandfeedinginnewborns.The overarchinggoalofthisProgramProjectistobetterunderstandtheDevelopmentalMechanismsofTrachea- EsophagealBirthDefectsinordertoadvanceourknowledgeoftheiretiology,enhancediagnosisandimprove treatment.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD093363-01
Application #
9403269
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Toyama, Reiko
Project Start
2017-08-15
Project End
2022-05-31
Budget Start
2017-08-15
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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