Assistant Investigator Center for Computational and Integrative Biology, Mass General Research Institute

Assistant Professor of Medicine Harvard Medical School

apolipoprotein a-i; atp-binding cassette transporters; avian myeloblastosis virus; cardiovascular disease; cholesterol; dna nucleotidyltransferases; hiv; lipoproteins hdl; nef gene products human immunodeficiency virus; polymorphism genetic; serine c-palmitoyltransferase

The Fitzgerald Laboratory research centers on cardiovascular disease, cholesterol metabolism and innate immunity. This effort is anchored by investigation of the efflux transporter ABCA1, which exports cholesterol and phospholipid from cells in the first step of HDL biogenesis. HDL is a lipoprotein whose blood level is inversely correlated with cardiovascular disease. Tangier patients with ABCA1 mutations develop premature vascular disease, peripheral neuropathies and lack circulating HDL. ABCA1 poly-morphisms are also of diagnostic interest, since they exert a strong influence on HDL levels in the general population.

Additionally, we investigate how HIV infection and antiretroviral treatment can alter HDL function and cardiovascular disease risk. Here the Fitzgerald Laboratory has developed methods to profile HDL from HIV positive individuals using mass spectrometry methods to quantitate protein and lipid content in this athero-protective lipoprotein. Additional work has analyzed how the HIV Nef protein reprograms macrophage lipid metabolism to maximize virion envelope production. Importantly, we have found that activation of the LXR nuclear hormone receptor strongly inhibits viremia in a humanized mouse model of HIV disease.

Finally, we are analyzing the mechanisms by which formation of cholesterol crystals in the artery wall can incite inflammatory processes through molecular pathways that involve a cellular multi-protein complex termed the “inflammasome”. This collaborative work with the laboratory of Eicke Latz has suggested cyclodextrin, a carrier molecule for hydrophobic drugs, has potential to be repurposed as an anti-atherosclerotic therapy that, in part, reprograms macrophage LXR transcriptional networks.