个人简介
I developed a keen interest in the biological aspects of chemistry during my last two years in high school in England, fuelled in large measure by completion of a Special Level paper in chemistry/biochemistry during my final year. After emigrating to Canada with my family, I was fortunate to spend the next summer working in the research laboratory of Dr. Allan Colter, then Chair of the department, where I carried out kinetic experiments on redox reactions of nicotinamide derivatives with quinones. This experience was extremely positive, and provided an impetus to continue on to graduate research. During the last year of my chemistry/biochemistry B.Sc. program, I became fascinated with biological membranes. The Singer-Nicolson fluid mosaic model had been proposed only a few years earlier, and had stimulated a flurry of research on membrane structure and dynamics. I decided that this was what I wanted to work on, held my breath, and jumped right in! My Ph.D. degree focussed on the applications of spin labelling to membrane glycolipids and glycoproteins, so I was introduced to biophysical techniques early in my career, and still continue with this approach today. With the advent of the massive gene sequencing era, membrane proteins have become even more interesting, since we are now able to relate their sequence and structure to their role in so many important biological processes. Membrane lipids have also risen to the forefront again, and are no longer regarded as a passive matrix for proteins, but as active players in membrane function. Today, my research group takes a multidisciplinary approach, using the tools of biochemistry, biophysics, molecular biology and cell biology, to explore how membrane proteins work at the molecular level. The involvement and interactions of membrane proteins with phospholipids, glycolipids, and cholesterol are also integral to our work.
I am a member of the Canadian Society for Molecular Biosciences (CSMB; where I am currently the Editor of the CSMB Bulletin), and the American Society of Biochemistry and Molecular Biology (ASBMB; where I served as a member of the Publications Committee). I have been a member of grant review panels at the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society Research Institute. I review manuscripts for several scientific journals, and I am currently an Editor for Biochemical Journal.
Education
B.Sc. Guelph
Ph.D. Western Ontario
研究领域
The research in my lab focusses on eukaryotic membrane proteins important in health and disease. The long-term goal is to understand the structure, function, and dynamics of these proteins at the molecular level, and to address their role in the normal functioning of the cell, as well as in disease states, such as cancer and genetic disorders. One important approach that we take is to study the purified membrane proteins following reconstitution into phospholipid bilayer vesicles. A variety of biochemical and biophysical approaches are then used to probe the molecule under study. Techniques in current use in our lab include fluorescence spectroscopy (both extrinsic fluorescence probes covalently linked to proteins or lipids, and intrinsic protein tryptophan fluorescence); NMR spectrometry, dynamic light scattering, differential scanning calorimetry, as well as biochemical assays for transport and enzymatic activity.
Areas of Research include:
Structure and function of the P-glycoprotein multidrug transporter:
This fascinating protein, which is a member of the ABC superfamily, acts as an ATP-driven efflux pump for chemotherapy drugs, thus contributing to multidrug-resistance in human cancer.
Structure and function of the bacterial lipid flippase, MsbA:
MsbA is the only essential ABC protein in Gram-negative bacteria, and may be an important antibiotic target. It is believed to act as a flippase for lipid A (and possibly phospholipids), moving it from the inner to the outer leaflet of the cytoplasmic membrane, where it is then incorporated into the bacterial outer membrane.
Lipid rafts and GPI-anchored membrane proteins:
Lipid rafts are specialized microdomains found in eukaryotic plasma membranes that are involved in many important cellular events. They act as "hotspots" for signal transduction, and also form "portals" for entry of pathogens such as viruses, toxins and bacteria. GPI-anchored proteins are clustered in the lipid rafts, anchored by tethering to a lipid molecule.
Molecular roles of the NPC1 protein in Niemann-Pick Type C disease:
NPC1 is involved in the intracellular trafficking of cholesterol, and a defect in this protein causes a fatal genetic disease characterized by the massive buildup of cholesterol in certain subcellular compartments.
近期论文
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Interaction of the P-Glycoprotein Multidrug Transporter with Sterols.
Clay AT, Lu P, Sharom FJ.
Biochemistry. 2015 Nov 3;54(43):6586-97. doi: 10.1021/acs.biochem.5b00904. Epub 2015 Oct 26.
Kinetic validation of the models for P-glycoprotein ATP hydrolysis and vanadate-induced trapping. Proposal for additional steps.
Lugo MR, Sharom FJ.
Complex Interplay between the P-Glycoprotein Multidrug Efflux Pump and the Membrane: Its Role in Modulating Protein Function.
Sharom FJ.
Reversible dimers of the atypical antipsychotic quetiapine inhibit p-glycoprotein-mediated efflux in vitro with increased binding affinity and in situ at the blood-brain barrier.
Emmert D, Campos CR, Ward D, Lu P, Namanja HA, Bohn K, Miller DS, Sharom FJ, Chmielewski J, Hrycyna CA.
Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication.
Munagala S, Sirasani G, Kokkonda P, Phadke M, Krynetskaia N, Lu P, Sharom FJ, Chaudhury S, Abdulhameed MD, Tawa G, Wallqvist A, Martinez R, Childers W, Abou-Gharbia M, Krynetskiy E, Andrade RB.
Bioorg Med Chem. 2014 Feb 1;22(3):1148-55. doi: 10.1016/j.bmc.2013.12.022. Epub 2013 Dec 21.
A semisynthetic taxane Yg-3-46a effectively evades P-glycoprotein and β-III tubulin mediated tumor drug resistance in vitro.
Cai P, Lu P, Sharom FJ, Fang WS.
Lipid bilayer properties control membrane partitioning, binding, and transport of p-glycoprotein substrates.
Determining P-glycoprotein-drug interactions: evaluation of reconstituted P-glycoprotein in a liposomal system and LLC-MDR1 polarized cell monolayers.
Melchior DL, Sharom FJ, Evers R, Wright GE, Chu JW, Wright SE, Chu X, Yabut J.
J Pharmacol Toxicol Methods. 2012 Mar;65(2):64-74. doi: 10.1016/j.vascn.2012.02.002. Epub 2012 Feb 26.
Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome).
Thompson MD, Roscioli T, Marcelis C, Nezarati MM, Stolte-Dijkstra I, Sharom FJ, Lu P, Phillips JA, Sweeney E, Robinson PN, Krawitz P, Yntema HG, Andrade DM, Brunner HG, Cole DE.
Am J Med Genet A. 2012 Mar;158A(3):553-8. doi: 10.1002/ajmg.a.35202. Epub 2012 Feb 7.
Proteins that bind and move lipids: MsbA and NPC1.
King G, Sharom FJ.
Crit Rev Biochem Mol Biol. 2012 Jan-Feb;47(1):75-95. doi: 10.3109/10409238.2011.636505. Epub 2011 Nov 26. Review.
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