Summary
This project aims to investigate the role of mitochondrial dysfunction and insufficient AMPK activity in genetically susceptible alveolar epithelial type 2 (AT2) cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and to test the potential of AMPK activators as therapeutics.
What they want
The project will advance understanding of the role of mitochondrial dysfunction in eliciting a pro-fibrotic AT2 cell phenotype, understand how disease-relevant environmental insults such as cigarette smoke exposure contribute to this dysfunction, and test its reversibility. Specifically, the role of insufficient adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation in driving AT2 cell mitochondrial dysfunction will be investigated, and the potential of AMPK activators as IPF therapeutics will be tested both in vitro and in vivo. This involves using patient-specific iAT2s carrying SFTPC and TERT variants, quantifying the relative contribution of cigarette smoke exposure using a novel model system, and leveraging an in vitro human platform to test the efficacy of AMPK agonists, with effective compounds then tested in vivo in the SftpcI73T mouse model.
Deliverables
- Advanced understanding of the role of mitochondrial dysfunction in eliciting a pro-fibrotic AT2 cell phenotype
- Understanding of how disease-relevant environmental insults (e.g., cigarette smoke exposure) contribute to AT2 cell dysfunction
- Data on the reversibility of AT2 cell mitochondrial dysfunction and the potential of AMPK activators as IPF therapeutics
Technical requirements
- Patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells (iAT2s)
- SFTPC and TERT variants
- Investigation of mitochondrial dysfunction, perturbed proteostasis, NF-κB pathway activation
- Investigation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation
- Novel model system for cigarette smoke exposure
- In vitro human platform for testing therapeutics
- SftpcI73T mouse model for in vivo testing
