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Dr. Marietta Jank - Best of the Best in Pediatric Surgery 2025
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What the experts said
Approximately 25% of CDH patients have concurrent cardiac anomalies.
CITED2 is a transcriptional modulator that can be induced by hypoxia, interleukins, interferon gamma, TNF alpha and LPS.
CITED2 binds with high affinity to coactivators regulating transactivation of multiple transcription factors including HIF-1 alpha, NF-kappa-B, PPAR gamma, and SMAD 2 and 3.
CITED2 null mutant mice and rats are embryonic and perinatal lethal, or in the case of rats die within the first few hours after birth, exhibiting lung and cardiac anomalies.
CITED2 is required for lung maturation and is detected in the septum transversum of the developing diaphragm.
At embryonic day 15 in the nitrofen rat model, there was no difference in CITED2 expression between CDH and control lungs.
At embryonic day 18, there was a decreased expression of CITED2 in nitrofen-induced CDH lungs, which was significant in in situ hybridization staining.
At embryonic stage 21, there was an increased expression of CITED2 in both in situ hybridization and on QPCR level in nitrofen-induced lungs.
Increased CITED2 staining was confirmed on a protein level in the epithelial layer of nitrofen-induced lungs.
Human fetal CDH lungs at late gestation showed a significantly increased abundance of CITED2 compared to controls, similar to the nitrofen model pattern.
Genomic sequencing of isolated CDH patients found a hotspot at the chromosomal coordinates for CITED2 on chromosome 6 compared to controls.
CITED2 may play a minor role in early lung development.
At E18, CITED2 may promote pulmonary maturation.
CITED2 orchestrates the inflammatory response in nitrofen-induced abnormal lung development at late gestation.
Proteomic data showed altered inflammatory pathways at E21 nitrofen lungs with increased abundance of CBP, NF-kappa-B and STAT3, which are all interacting factors of CITED2.
CITED2 may be induced by NF-kappa-B signaling and acts as a negative feedback regulation of NF-kappa-B in the nucleus.
The research team is collaborating with Kansas University for a CRISPR-Cas9 CITED2 mutant rat to investigate lung morphology throughout development.
CITED2 expression is low at early lung development according to literature.
CITED2 deficient mice showed no difference in lung phenotype compared to controls at embryonic day 16.5.
CITED2 null mutant mice embryos at E17.5 and 18.5 showed signs of pulmonary immaturity with smaller lobe size, increased percentage of tissue and loss of air space.
CITED2 mutant rats showed arrest at canalicular stage.
CITED2 itself is induced by proinflammatory stimuli like LPS, interleukins, interferon gamma and TNF alpha according to current literature.