Determining the mechanistic role of gremlin 1 in the profibrotic activation of monocyte-derived macrophages and in the pathogenesis of idiopathic pulmonary fibrosis

The problem: Idiopathic pulmonary fibrosis (IPF) is a rare, progressive lung disease resulting in respiratory failure. IPF is irreversible and patient’s median survival is 3-5 years post-diagnosis. The only curative recourse is lung transplantation because nintedanib and pirfenidone, the only two treatment options slow disease progress but do not cure or cause disease regression. Specific depletion of profibrotic monocyte-derived macrophages (MDMs) protects mice against pulmonary fibrosis suggesting a causal role for MDMs in disease development. While these depletion approaches can be undertaken experimentally, they cannot be performed in humans because MDMs are required for normal immunity. Thus, a targeted blockade of the mechanisms causing excessive profibrotic activation of MDMs is required to develop novel therapeutic approaches. The discovery: My proposal arises from the Host's recent finding that depletion of the bone morphogenetic protein antagonist GREM1 in mouse MDMs inhibits their profibrotic activation.The proposal: My proposed work will determine whether targeted deletion of GREM1 in human MDMs inhibits their profibrotic activation and prevents pulmonary fibrosis in an animal model.The objectives: To evaluate the above, I have identified two specific objectives (SO):SO1. Determine the precise roles of endogenous and exogenous GREM1 in regulating the profibrotic activation of MDMs derived from IPF patients and healthy controlsSO2. Determine whether GREM1 deletion in MDMs protects against pulmonary fibrosis in an animal model The outcomes: I will determine the role of MDM-derived GREM1 in pulmonary fibrosis potentially identifying a new therapeutic approach. I will receive critical training in a world-class institution, allowing my research to span clinical and pre-clinical studies to in-vivo imaging and omics techniques. The scientific and transferable skills I will obtain are essential for a successful academic or non-academic career.