Screening of novel compounds through the reversal of gene expression in idiopathic pulmonary fibrosis

PROJECT SUMMARY / ABSTRACT Fibrosis of the lung is a pathological condition resulting from injury to the lung and an ensuing fibrotic response; its most common form is Idiopathic Pulmonary Fibrosis (IPF). Fibrosing lung diseases lead to thickened alveolar walls and the obliteration of the alveolar space with generally unknown etiology. There are currently no effective therapies for IPF and the median survival for IPF patients after diagnosis is approximately 3 years. The FDA approved Pirfenidone and Nintedanib for the treatment of IPF. Both drugs reduce disease progression but neither drug reverses lung fibrosis nor prevents death. Lung transplantation becomes the only effective therapy for IPF patients and approximately 40,000 patients die annually from IPF in the U.S.A. Thus, there is an urgent need for effective therapies for IPF and other fibrosing lung diseases. Recent evidence suggests that distal small airways are involved in the early pathogenesis of IPF. Small airways are defined as diameter less than 2mm in adult human lungs. Our recent studies demonstrated that ATP12A (a non-gastric proton pump) is upregulated in IPF small airways and has profibrotic roles in IPF. The small airways in IPF consist of several distinct cell types, and the contribution of each to the pathogenesis of IPF remains largely unknown. Recent advances in multiplexed single-cell RNA sequencing (scRNA-seq) and the reduction in scRNA-seq costs have allowed for large-scale profiling of small airway cells, enabling the characterization of cellular and molecular features of IPF. However, understanding the role of individual features is challenging, if not impossible. Therefore, we propose a transcriptomics -based approach to identify drugs that can reverse the global expression of cell-type-specific transcriptional features. Our hypothesis is that small molecules that reverse profibrotic gene signatures in IPF can reduce lung fibrosis. We propose 3 specific aims. Aim 1: In silico discovery of drugs and novel compounds for IPF using a transcriptomics-based approach. Aim 2: Discover three lead compounds that have anti-fibrotic effects in IPF lung explant. Aim 3: Examine if the top one lead compound has anti-fibrotic effects in experimental models of IPF. The large-scale single cell profiling of lung tissues and the evaluation of artificial intelligence (AI)-informed drug candidates in clinically relevant models could lead to the discovery of effective therapeutic approaches for IPF.