What is it about?
NOTCH3 is the crucial signaling deliverer of the pro-proliferative mTOR command. Number of research works showed that NOTCH3 upregulation is responsible for the hypoxic PAH remodeling. Reversal of remodeling by NOTCH3 inhibition was achieved using Rapamycin, inhibiting mTOR up-stream of NOTCH3, or using DAPT ( secretase inhibitor) in direct NOTCH3 inhibition. In our further study we explored also in vitro and in vivo use of DAPT in reduction of PASMC proliferation in the neonatal chronic hypoxia model of PAH.
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Why is it important?
Prior to our research work, NOTCH3 signaling and autophagy was not yet explored in neaonatal PAH. Also a connection was found between NOTCH3 signaling and PDGFRB signaling.
Perspectives
Next, rescue study should be tested, to see whether there is a curative potential of NOTCH3 inhibition on PAH when PAH is already established. If reversal effect is established, then next to be explored should be systemic effects of NOTCH3 inhibitors. And the final most important direction of this research would be translation to human medicine.
Julijana Ivanovska
Hospital for Sick Children, PGCRL, Toronto, Ontario
Read the Original
This page is a summary of: mTOR-Notch3 signaling mediates pulmonary hypertension in hypoxia-exposed neonatal rats independent of changes in autophagy, Pediatric Pulmonology, July 2017, Wiley,
DOI: 10.1002/ppul.23777.
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