Determining the role of CD163+ blood monocytes and lung macrophages in Progressive Pulmonary Fibrosis

/ABSTRACT Sarah Holton, MD, PhD plans for a career as a physician-scientist in the fields of human immunology and fibrotic interstitial lung disease. Support from this K23 Career Development Award will provide necessary training in development of patient cohorts, statistical approaches, and methods for the analysis of single cell and spatial transcriptomic datasets. The training plan described will complement Dr. Holton’s basic science and engineering background and facilitate her transition to independent research. The proposal leverages Dr. Holton’s unique access to both the Benaroya Research Institute’s expertise in Immunology and Bioinformatics and the University of Washington’s expertise in lung biology and Interstitial Lung Disease as well as access to clinical samples and mentorship at both sites. The proposal focuses on the role of alveolar/interstitial macrophages and peripheral blood monocytes in the development of Progressive Pulmonary Fibrosis. These patients have limited therapeutic options that do not improve lifespan, and their 5 year survival is only 50%. It is critical to identify the mechanisms that lead to development of fibrosis in order to develop therapies targeted to intervene at early disease stages. We leverage our expertise in isolating and characterizing human alveolar macrophages and peripheral blood monocytes, an existing pulmonary diseases biorepository that contains paired alveolar, blood, and lung tissue samples, and recruiting a prospective cohort of patients from the UW Center for Interstitial Lung Disease. In this patient-oriented research plan, Dr. Holton will use these resources to address her hypothesis that CD163+ alveolar macrophages and peripheral blood monocytes are associated with the development of Progressive Pulmonary Fibrosis and have pro-fibrotic transcriptional programs. Dr. Holton will address these hypotheses through the following three aims: 1) Test for associations between CD163+ alveolar macrophages and progressive pulmonary fibrosis in patients with fibrotic ILD in existing samples using flow cytometry, 2) Establish the spatial and transcriptional relationship between CD163+ macrophages and regions of fibrosis in biopsy samples isolated from patients with early fibrotic ILD using spatial transcriptomics, and 3) Identify how the peripheral blood CD163+ monocyte population changes over time and how that is associated with PPF in a prospectively recruited cohort. Dr. Holton will also uncover the potential mechanism in which these cells contribute to fibrosis using in vitro models. The findings of these studies will have direct patient impact and will provide Dr. Holton with the infrastructure and skills necessary to submit an R01 proposal by Year 4 of her proposed K23 funding period. The research outlined in this proposal will serve as the foundation to growing a rich clinical biobank of samples from patients with ILD so that Dr. Holton can continue her research in defining the contribution of macrophage and other immune cell populations to fibrotic lung disease. Project Number: 1K23HL175120-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Sarah Holton | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $188,892 | Activity Code: K23 | Study Section: NHLBI Mentored Patient-Oriented Research Study Section[MPOR (MA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL17512001A1