PROJECT SUMMARY/ABSTRACT Fibrosis is a common final outcome of most human chronic inflammatory diseases and has been estimated to contribute to almost half of all deaths in the world 1. It can result from autoimmune diseases such as scleroderma, after stem cell transplant in graft-vs-host disease, from chronic inflammatory conditions associated with obesity and diabetes and through inherited genetic disorders. Fibrosis can affect virtually any organ including the skin, lungs, kidneys, liver, heart and blood vessels. Scleroderma and graft-vs-host disease most commonly affect the skin and the degree of skin involvement is associated with higher mortality and internal organ dysfunction 2,3, suggesting common underlying mechanisms. We previously identified in these diseases activation of epidermal growth factor receptor (EGFR) on fibroblasts by its immune cell derived ligand epiregulin. This proposal aims to further elucidate the major gaps in our knowledge of how EGFR signaling drives fibrosis in the skin. In particular, it is unclear what signaling pathways downstream of EGFR activation are critical to different phases of fibrosis and how these targets cross-talk with other fibrosis-associated pathways. In this project, we examine the cellular signals that result from chronic EGFR activation in fibroblasts and pericytes and their cross-talk with STAT1, an essential transcription factor for regulating interferon-dependent gene expression. In our first aim, we will characterize the effects of EGFR activation in fibroblasts and pericytes using a Tet-On expression system. This model system will allow temporal and cell-type control of EGFR activation in vivo. We will analyze what EGFR pathways are activated and required for development of skin fibrosis, and their effects on the immune system. In the second aim, we will examine the relevant cell types in which STAT1 signaling is required for development of fibrosis using bone marrow chimeras and STAT1 conditional knockout mice. We will investigate whether EGFR and STAT1 signaling are co-dependent and utilize proteomics techniques to discover protein interactions and modifications. Together, these aims will provide better insight into the pathogenesis of fibrotic skin disease, lead to a broader understanding of fibrosis as a biological process, and help develop new treatments that may substantially impact patients' lives.