Integrating Omics, Networks, and Functional Studies in COPD and IPF

PROJECT SUMMARY The variable development of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) among smokers could relate to genetic variants, epigenetic determinants, environmental factors, or their interactions. Rather than operating in isolation, genetic and epigenetic determinants of COPD and IPF likely influence molecular networks of interacting genes and proteins. Based on progress in murine and human studies in the first cycle of this PPG, we will focus on mitochondrial and chitinase pathways as potential molecular switches that impact whether individuals develop COPD or IPF. We hypothesize that a molecular network of genetic and epigenetic determinants regulating mitochondrial and chitinase proteins confers differential susceptibility of smokers to develop COPD or IPF. In addition, we hypothesize that mitochondrial and chitinase pathways influence the heterogeneous manifestations of COPD and IPF. In order to investigate the differential susceptibility to develop COPD and IPF and the impact of these pathways on COPD and IPF subtypes, we will leverage our human population-based and genetic/epigenetic resources in COPD and IPF, including the Lung Tissue Research Consortium (LTRC) and multiple replication populations. We will measure a panel of chitinase and mitochondrial pathway proteins in plasma and lung biospecimens and test for their association with COPD and IPF and their related phenotypes. We will identify genetic variants, mitochondrial characteristics, and DNA methylation marks that influence expression of chitinase and mitochondrial pathway proteins in lung and blood samples and determine whether these variants are also associated with COPD and/or IPF. We will identify network relationships within and between the mitochondrial and chitinase pathways by using correlation-based networks, gene regulatory networks, and protein-protein interaction networks. Key network relationships within and between mitochondrial and chitinase pathways will be validated using CRISPR-based functional approaches in lung epithelial cells, monocyte-macrophages, and fibroblasts with readouts of cell death, fibrosis, chitosome components, mitochondrial function, and inflammation to identify shared and divergent network determinants of IPF and COPD.