Modeling to Design Treatments for Idiopathic Lung Fibrosis

点击翻译按钮获取中文摘要

PROJECT SUMMARY Every year in this country 40,000 patients are diagnosed with idiopathic pulmonary fibrosis (IPF), a progressive and terminal disease caused by excessive extracellular matrix production by myofibroblasts in distributed lesions, or “fibrotic foci”, throughout the lung. Despite the availability of two FDA-approved drugs that are considered standard of care, the mortality rate for IPF patients exceeds 30% at four years, and there are no drugs that halt disease progression, making diagnosis with IPF a death sentence for over 500,000 Americans living with this disease. Identifying the cells of origin that give rise to myofibroblasts is necessary for finding treatments that can halt or cure IPF. Based on experimental data and computational simulations from our research team, we hypothesize that myofibroblasts arise from microvascular pericytes (cells that normally enwrap capillaries) when heterotypic pericyte-endothelial interactions become disrupted. We further posit that strategic modulation of kinase-mediated signaling in pericytes can prevent pericyte-to-myofibroblast transitions and halt the progression of IPF. We propose to combine computational modeling with experiments to study pericyte-to-myofibroblast differentiation and to investigate how microvessel adaptations in the lung contribute to IPF. Specifically, we will develop a new agent-based model (ABM) that incorporates logic-based intracellular signaling networks to simulate cell behaviors and leverages Bayesian inference for rule refinement (Aim 1), validate the ABM's ability to predict pericyte phenotype transitions and the emergence of fibrotic foci in response to drugs using the murine bleomycin model of IPF (Aim 2), and bridge murine experiments with clinical data in order to predict how druggable kinase-driven signaling pathways affect IPF progression via modulation of pericytes and microvessels (Aim 3). To our knowledge, our proposed studies will be the first to combine computational modeling with experiments to study microvascular contributors to IPF progression. In addition to producing a new computational model that is validated for bridging pre-clinical study results to clinical outcomes, we expect to identify new therapeutic approaches for IPF that target microvascular cells, previously underexplored but potentially critical contributors to this deadly disease.