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Principal Investigator: BERNICE E MORROW
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $579,364
Funding agency: National Heart Lung and Blood Institute
Project Summary
Cardiac outflow tract (OFT) defects have an estimated prevalence of 1-2 in 1,000 live births. The
22q11.2 deletion syndrome or 22q11.2DS is one of the most frequent genetic causes of cardiac OFT defects. A
total of 60% of patients with 22q11.2DS have congenital heart disease that ranges from mild to severe including
bicuspid aortic valve (BAV), isolated ventricular septal defects (VSDs) to tetralogy of Fallot (TOF) or persistent
truncus arteriosus (PTA). These clinical findings suggest genetic modifiers may affect phenotypic expression
. In
this project, we propose to use the Lgdel/+ mouse model to understand the relationship between neural crest
cells (NCCs) and adjacent endocardial cells (ECCs) in forming and remodeling of the cardiac OFT.
Mesenchymal cells (MCs) derived from NCCs and ECCs occupy the distal and proximal OFT, respectively, and
form a distinct OFT MC boundary during heart development. Proper deployment of MCs from the two lineages
ensures correct position and formation of aorto-pulmonary-ventricular septum and semilunar valves to separate
the heart outlet into the systemic and pulmonary circulation. The function of NCCs in OFT defects has been well
studied with respect to 22q11.2DS, however, the role of ECCs in OFT malformations has not been investigated.
We have begun to fill this knowledge gap by studying the Lgdel/+ mouse, which was generated by deleting one
copy of the mouse syntenic region of human 22q11.2 containing 26 protein-coding genes (22q11.2DS genes).
We found a spectrum of OFT defects ranging from isolated VSD to TOF. The structural defects are preceded by
a disrupted OFT MC boundary, increased expression of Edn1 during endocardial-to-mesenchymal
transformation (EMT), and decreased NOTCH1 signaling and Ctgf expression during post-EMT OFT remodeling.
By single cell RNA sequencing (scRNA-seq), we identified Edn1 as part of a unique gene program operating in
a subset of ECCs undergoing EMT. Based on these findings, we propose an overall hypothesis that 22q11.2DS
genes control OFT development by regulating the function of ECCs and the cell-cell communications between
MCs from ECC and NCC origins, via interacting with genes essential for OFT formation. We will test this
hypothesis in three specific aims. Aim 1 will determine whether the 22q11.2DS genes regulate EMT through
modulating the EMT gene program, and if Edn1 acts downstream of 22q11.2DS genes to regulate the process.
Aim 2 will ascertain whether 22q11.2DS genes also regulate OFT remodeling through a cell-cell interaction
network that patterns the OFT MC boundary, and if Ctgf functions as a hub gene required for the post-EMT OFT
remodeling, downstream of 22q11.2DS genes. Aim 3 will define whether Notch1 haploinsufficiency can
potentiate the 22q11.2DS OFT defects. At the completion of this study, we expect discoveries that will establish
genetic, molecular, and cell crosstalk regulated by important syndromic and non-syndromic CHD genes essential
for mouse OFT morphogenesis. The information will provide deeper understanding of heart developmental
biology and inform the disease mechanism of OFT defects, with a broader implication in congenital heart
disease.
Terms: <0-4 weeks old><22q11><22q11 Chromosomal Microdeletion Syndrome><22q11 Deletion Syndrome><22q11.2><22q11.2 deletion syndrome><22q11.2DS><22q11DS><3-D><3-Dimensional><3D><Affect><Assay><Autosomal dominant Opitz G/BBB syndrome><Bioassay><Biological Assay><Body Tissues><CCN2><CTGF><Cardiac><Cardiac Malformation><Cardiac Septum><Cardiac development><Cayler cardiofacial syndrome><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Lineage><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Chromosome 22q11.2 deletion syndrome><Clinical><Code><Coding System><Defect><Development><Developmental Biology><Di George syndrome><DiGeorge Syndrome><DiGeorge anomaly><DiGeorge sequence><Disease><Disorder><Distal><Drosophila Homolog of NOTCH 1><EDN1><ES cell><ET-1><Early identification><Embryo><Embryonic><Endocardium><Endothelin Type 1><Endothelin-1><Ensure><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Heart><Heart Malformation><Heart Septum><Histology><Human><IGF-binding protein-related protein-2><IGFBP-8><IGFBP-rP2><Immunofluorescence><Immunofluorescence Immunologic><In Situ Hybridization><Intervention><Intervention Strategies><Interventricular Septum><Intracellular Communication and Signaling><Knowledge><Live Birth><Medical><Mesenchymal><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morphogenesis><Murine><Mus><Mutation><NOTCH1><NOTCH1 gene><Neural Crest><Neural Crest Cell><Neural tube><Neurophysiology - biologic function><Newborn Infant><Newborns><Outcome><Patients><Pattern><Persistent Truncus Arteriosus><Phenotype><Population><Position><Positioning Attribute><Prevalence><Process><Progenitor Cells><Proteins><Pulmonary Circulation><R-Series Research Projects><R01 Mechanism><R01 Program><Research Grants><Research Project Grants><Research Projects><Role><Sedlackova syndrome><Shprintzen syndrome><Signal Transduction><Signal Transduction Systems><Signaling><Structural defect><Structural malformation><Structure><TAN1><Testing><Tetralogy of Fallot><Tissues><Translocation-Associated NOTCH Homolog><Validation><Ventricular Heart Septal Defects><Ventricular Septal Defects><Ventricular septum><abnormal heart development><allele variant><allelic variant><bicuspid aortic valve><biological signal transduction><cardiogenesis><cell motility><congenital cardiac abnormality><congenital cardiac anomalies><congenital cardiac disease><congenital cardiac disorder><congenital cardiac malformation><congenital heart abnormality><congenital heart anomaly><congenital heart disease><congenital heart disorder><congenital heart malformation><connective tissue growth factor><conotruncal anomaly face syndrome><developmental><embryonic progenitor><embryonic stem cell><experiment><experimental research><experimental study><experiments><familial third and fourth pharyngeal pouch syndrome><fisp12 protein><gene interaction><gene signatures><genetic signature><genetic variant><genome mutation><genomic variant><heart development><heart formation><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><insulin-like growth factor binding protein 8><interventional strategy><malformation><morphogenetic process><mouse model><murine model><mutant><neural function><newborn child><newborn children><pharyngeal pouch syndrome><progenitor cell function><progenitor function><programs><reconstruction><restoration><scRNA-seq><semilunar valve><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem and progenitor cell function><stem and progenitor function><stem cell function><stem cell of embryonic origin><stem cells><structural abnormalities><structural anomalies><third and fourth pharyngeal pouch syndrome><three dimensional><thymic and parathyroid agenesis syndrome><validations><velo-cardio-facial syndrome><velocardiofacial syndrome><velofacial hypoplasia>