PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is an incurable, progressive chronic respiratory disease, and a leading cause of death in the United States. COPD is a heterogenous syndrome, characterized by diverse clinical and pathologic manifestations of COPD that vary amongst susceptible individuals. Growing evidence suggests COPD is characterized by the presence of aberrant cell populations that can be identified using single-cell sequencing technologies. The overarching goal of this proposal is to provide a deeper understanding of how these aberrant cells communicate with their microenvironment and identify novel strategies for therapeutic intervention. Our overarching hypothesis is that COPD heterogeneity is due to aberrant cell-cell and cell-matrix communication that occur to varying degrees in susceptible individuals. In Aim 1, we will identify aberrant cell- cell signaling by performing network level analyses of a newly created dataset of single-nuclear RNA sequencing data generated with frozen lung tissue samples from the Lung Tissue Research Consortium (LTRC). We will then use spatial transcriptomics from the same samples to provide spatial context to these signaling pathways and refine our understanding of aberrant cell-cell signaling in COPD. In Aim 2, we will assess cell-matrix communication networks by performing proteomic profiling of decellularized lung tissue samples from the same LTRC samples and perform network level analyses to assess cell-matrix interactions that are enriched in disease or correlate with disease traits. By assessing spatial cell-cell interactions, and aberrant cell-matrix networks, we hope to identify novel therapeutic targets for COPD. This proposal is a response to the Funding Opportunity Announcement (FOA) to support meritorious exploratory research relevant to the NHLBI mission using the existing biospecimen collections that are stored in the NHLBI Biologic Specimen Repository (Biorepository), thereby maximizing the scientific value of the stored collections, and providing researchers with an opportunity to generate preliminary data for subsequent research proposals. Findings from this proposal will be utilized for further mechanistic investigation of potential therapeutic targets.

PROJECT NARRATIVE Chronic obstructive pulmonary disease (COPD) is a leading cause of death in the United States for which there is no cure. In this study, we will utilize high-throughput RNA sequencing technologies, proteomics, spatial profiling, and network analyses to understand how aberrant cells in COPD communicate with their local environment. We believe that this may identify new therapeutic targets for COPD.