Lolis Lab Research
Studies on proteins involved in inflammation, cancer, and infectious disease
Our laboratory is interested in the mechanisms of proteins involved in cancer, inflammation, and parasitic infections. To carry out our research goals we follow a multi-disciplinary strategy making use of X-ray crystallography, nuclear magnetic resonance (NMR), mice models, high-throughput screening of small molecule ligands, and a number of other biophysical and biochemical techniques (the equipment we use is illustrated here). The focus in the last several years has been on chemokines, chemokine receptors (GPCRs), and the pro-inflammatory proteins macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) expressed in humans and in a variety of disease parasites.
Chemokines are secreted proteins that activate G-protein coupled receptors to mediate the migration of specific cells to the appropriate anatomical locations in response to physiological signals (homeostasis) and pathophysiological insults (immunity). Some of the >40 human chemokines have roles in embryonic development or homeostasis, while most cause inflammation, autoimmune diseases, or cancer metastasis.
G-protein coupled receptors (GPCRs) belong to a family proteins that counts more than 800 human members, with a characteristic seven transmembrane domain. Binding of chemokines to specific GPCRs triggers a cascade of intracellular signaling events mediated by the exchange of GDP by GTP on the Gα protein and its disassociation from the GPCR and from Gβγ.
We complement these studies with research using a strain of S. cerevisiae altered to express functional chemokine receptors that are activated by specific chemokines.
We have determined the X-ray structures of human and parasitic MIF. Human MIF is a pro-inflammatory protein involved in sepsis, rheumatoid arthritis and other autoimmune disease, and cancer. Parasitic MIF appear to interfere or regulate the endogenous MIF and provide parasites a survival advantage.