Epithelial cell mediated fibroblast activation through CTHRC1-TGFb signaling in fibrotic lung diseases

ABSTRACT Fibrotic lung diseases represent a heterogeneous group of diseases resulting from a variety of genetic defects, immune conditions, or inhalational exposures. Fibrosis can manifest in the lung airways in the form of bronchiolitis obliterans (BO) or in the lung parenchyma as in idiopathic pulmonary fibrosis (IPF). Effective pharmacological treatments are lacking for lung fibrosis. As a result, fibrotic lung diseases such as BO and IPF are associated with high morbidity and mortality, and understanding mechanisms of lung fibrosis represents a critical area of need. In this proposal we seek to answer a fundamental question in lung fibrosis – what are the mechanisms that lead to fibroblast activation from normal pulmonary fibroblasts to abnormal fibroblast populations. Supported by novel preliminary data, we identified CTHRC1, a secreted glycoprotein, as important not only as a marker of fibroblast activation, but as a key regulator of fibroblast activation upstream of TGFβ signaling, an important pathway implicated in fibrosis phenotypes. In Aim 1, we will evaluate important airway epithelial cell-fibroblast interactions contributing to CTHRC1- mediated fibroblast activation in the context of bronchiolitis obliterans, a fibrotic airway disease. In Aim 2, we will evaluate alveolar epithelial cell-fibroblast interactions contributing to CTHRC1- mediated fibroblast activation in the context of idiopathic pulmonary fibrosis, a fibrotic lung parenchymal disease. We will leverage Duke University’s status as one of the largest lung transplant centers to directly investigate these questions in human explanted lungs using single cell and spatial transcriptomic analysis as well as sophisticated primary human cell culture techniques. These studies will demonstrate a common mechanism of fibroblast activation in different lung fibrotic diseases and identify a novel therapeutic target in CTHRC1 and its downstream effectors for treatment of fibrotic lung disease. The data gathered during this award period coupled with ongoing mentorship and a multi-disciplinary research environment will prepare me to fulfill my long-term goal of becoming an independent physician-scientist.