Role of GM-CSF and impaired lipid metabolism in the pathogenesis of PAP

PROJECT SUMMARY/ABSTRACT Dr. Elinor Lee is a Pulmonary and Critical Care physician who is greatly interested in the role of lipid metabolism in surfactant homeostasis and pulmonary diseases. Dr. Lee is focused on mechanistic studies exploring the paradigm-shifting hypothesis that lipid dysregulation contributes to the pathogenesis of pulmonary alveolar proteinosis (PAP). Her long-term goal is to establish an independent research program as a physician scientist in the field of lipid biology and PAP and eventually, other pulmonary diseases. She is supported by her primary mentor, Dr. Tarling, a leader in lipid biology and inflammation, as well as her co-mentors and advisors who will provide their multidisciplinary expertise in training Dr. Lee in the theoretical and technical aspects of lipid metabolism and immunology. Through UCLA’s Clinical and Translational Science Institute (CTSI), Dr. Lee will have access to numerous career development seminars that address such topics as grant writing, manuscript preparation, and ethical research. She will also take graduate courses to obtain further training in gene editing, immunology, lipid metabolism, and biostatistics. Dr. Lee has the full support of her institution to carry out her research. This proposal outlines a 5-year research and career development plan that will prepare Dr. Lee to become an independent physician-scientist engaged in cutting-edge scientific research. This project aims to elucidate the mechanisms by which loss of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling impairs clearance of surfactant in alveolar macrophages. Dr. Lee’s prior work suggests that reduced expression of GM- CSF-dependent ABCG1, an intracellular cholesterol transporter that requires ATP to function, may drive reductions in cholesterol export by alveolar macrophages. Recent evidence, however, also suggests that reduced ATP production caused by impaired GM-CSF-dependent fatty acid catabolism may contribute to reduced phospholipid catabolism and/or cholesterol clearance. In Specific Aim 1, Dr. Lee will define the temporal sequence and kinetics of lipid abnormalities caused by loss of GM-CSF stimulation in vivo with a novel, inducible mouse model to identify the primary, pathogenic lipid abnormality and the secondary changes. Further, she will evaluate whether reducing cholesterol content in alveolar macrophages will restore their function to demonstrate that cholesterol accumulation due to impaired cholesterol clearance is the primary pathologic defect driving alveolar macrophage dysfunction seen in PAP. Aim 2 will focus on determining the mechanism of the primary and secondary lipid abnormalities caused by impaired GM-CSF signaling. Improved understanding of the relationship between loss of GM-CSF signaling and lipid dysregulation leading to surfactant accumulation will be crucial to the development of effective, innovative therapeutic strategies for patients with PAP and enhancing the fundamental knowledge of alveolar macrophages.