National Heart, Lung, and Blood Institute 1R01HL179063-01A1

Targeting the fibrogenic ECM as an alternative approach to treating IPF

NIH awarded a grant to University of Virginia to research fibronectin's role in lung fibrosis and develop therapeutic antibodies targeting fibrogenic ECM in IPF.

Description

This proposal focuses on establishing a novel therapeutic target, the molecular mechanisms of its disease-driving properties, and the therapeutic efficacy of blocking the target in the context of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis are wound healing disorders characterized by unorganized and unchecked extracellular matrix (ECM) deposition leading to scarring and stiffening of the lung interstitium. The process involves activated fibroblasts, myofibroblasts, and contributions from various cell types. Recent findings demonstrate that stretch-dependent conformational changes in fibronectin trigger an integrin switch, activating fibroblasts and promoting fibrogenesis. This project hypothesizes that fibronectin's stretch-dependent conformational change is a marker of active fibrogenesis and disrupts normal cell-ECM interactions, leading to disease progression. The research aims to quantify this conformational change in patient tissues, elucidate the molecular mechanisms involved, and explore therapeutic interventions using antibody drugs.

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