SummaryChronic epithelial or vascular injuries followed by dysregulated repair are the trigger mechanisms inpathogenesis of interstitial lung diseases including idiopathic pulmonary fibrosis (IPF). Multiple cell types areinvolved in lung fibrogenesis with fibroblasts and epithelial cells given the most attention. Role of endothelialcells and microvasculature remain unclear. Dysregulated repair causes vascular remodeling associated withincreased vessel permeability partial loss of capillaries focal increase in pathological angiogenesis andendothelial dysfunction. Normal endothelial cells (EC) are transcriptionally re-programmed into fibrosis-associated endothelial cells (FEC) that support activated fibroblasts and promote lung inflammation. Our long-term goal is to identify key regulators of EC-to-FEC re-programming and clarify molecular mechanisms of thecrosstalk between endothelial cells and other cell types during pulmonary fibrogenesis. In our preliminary datawe used endothelial cells from lungs of patients with IPF and mouse lung fibrosis models to identify FOXF1 asa key transcriptional regulator of EC-to-FEC re-programming during lung fibrogenesis. Using transgenic mousemodels with endothelial-specific deletion or over-expression of Foxf1 gene we propose to test the hypothesisthat endothelial FOXF1 decreases activation of fibroblasts and prevents macrophage accumulation in fibroticfoci. We propose two specific aims: (1) identify molecular mechanisms whereby endothelial FOXF1 inhibitslung fibrogenesis (2) establish whether restoring FOXF1 in FECs will prevent or reduce fibrotic lungremodeling after chronic lung injury. Understanding the regulation of EC-to-TEC re-programming and themolecular mechanisms utilized by pulmonary endothelial cells to control pulmonary fibrosis will provide newapproaches for treatment of interstitial lung diseases.