Dr. Fessler’s laboratory investigates mechanisms by which cholesterol trafficking regulates the innate immune response to environmental challenges, with a focus on the macrophage and the lung. The central hypothesis is that host cell responses to self-derived lipids and microbial lipids (e.g., lipopolysaccharide) are intrinsically coupled through conserved molecular pathways deriving from common ancestral roots. The prediction of this model is that study of host cell lipid homeostasis will provide fundamental insights into the induction and regulation of innate immunity, as well as into determinants of the inflammatory phenotype in humans. To this end, Dr. Fessler’s laboratory has undertaken: 1) hypothesis-directed and exploratory (i.e., proteomic) approaches to the role of lipid rafts in Toll-like Receptor signaling in leukocytes; 2) in vivo (mouse model) studies of the role of cholesterol pathway regulation in pulmonary immunity; and 3) translational and epidemiologic investigations of the relationship between serum cholesterol levels and inflammatory lung disease in humans. In a separate arm of his research program, Dr. Fessler has also defined novel roles for the tumor suppressor p53 in regulation of the innate immune response, work that has translational implications for both host defense and cancer.