Alveolar macrophage and epithelial cell lipid metabolism in pulmonary fibrosis

PROJECT SUMMARY Richard Watson, MD, PhD, is a Clinical Instructor of Medicine in the Division of Pulmonary and Critical Care Medicine at the University of California, Los Angeles (UCLA). His clinical and research interest is in idiopathic pulmonary fibrosis (IPF), a disease that results in the progressive, irreversible scarring of the lung and has no curative treatment. A five-year research career development plan is proposed, focused on determining the mechanisms of lipid metabolism in IPF, which will serve to establish Dr. Watson’s independent translational research program. This proposal builds upon his strong basic science background and provides new training in epithelial biology, next-generation sequencing techniques, bioinformatics, and translational research utilizing human patient samples. During the award term, Dr. Watson will be mentored by Dr. Steven Bensinger, a leader in the field of immunometabolism and lipid biology with a track record of mentoring over 15 graduate students, post-doctoral fellows, and junior faculty to independent careers in biomedical research. He will have additional support from co-mentor Dr. Steven Dubinett, a world-renowned lung cancer immunologist, and a strong team of advisors with diverse but complementary areas of expertise. During his post-doctoral training, Dr. Watson established an innovative research platform that leverages advanced mass spectrometry-based techniques with a series of loss-of-function genetic murine models. Using this unique system, Dr. Watson has begun to mechanistically dissect the intricate, lipid-rich metabolic circuit represented by the distal airway. Dr. Watson has demonstrated that the lipid metabolic state, or lipidome, of the alveolar macrophage (AM) is dramatically reprogrammed during IPF pathogenesis. This is characterized by the generation of monounsaturated fatty acids (MUFAs) through the upregulation of the lipogenic enzyme stearoyl- CoA desaturase (SCD), which serves as a protective factor against pulmonary fibrosis. In this proposal, Dr. Watson aims to study the complex metabolic relationship between AMs and alveolar epithelial type II cells (AT2s). Aims 1.1 & 1.2 build upon preliminary in vitro data indicating that SCD functions through cREL and NFκB to modulate proinflammatory signaling and seek to determine how changes in macrophage lipid composition relay information to the cell’s epigenome and transcriptome. Aim 1.3 utilizes human IPF biospecimens and multiplex immunofluorescence technology to determine the spatiotemporal regulation of macrophage SCD in IPF pathogenesis. Aim 2.1 of the proposal leverages a novel in vitro co-culture organoid system that can recapitulate much of the complexity of the alveolar space, allowing rapid screening of small- molecule inhibitors that may have therapeutic potential for treating IPF. Aims 2.2 & 2.3 will utilize a series of lineage-specific genetic murine models to mechanistically dissect the fatty acid biosynthetic pathway in AMs and AT2s and their symbiotic relationship in the airway. Completion of these aims will mechanistically advance our understanding of the lipid metabolic circuitry of AMs and AT2s in IPF.