Alasdair M. Gilfillan, Ph.D.
Assistant Section Chief
Dr. Gilfillan received his Ph.D. from the University of Manchester, U.K., then did his postdoctoral training at Yale University Medical School. Following a number of years spent conducting pre-clinical research at Hoffmann La-Roche in the areas of allergy and inflammation, he joined the Mast Cell Biology Section of the Laboratory of Allergic Diseases in 1999. Dr. Gilfillan has had a long-standing interest in signaling pathways associated with receptor-mediated activation of mast cells.
Description of Research Program
The primary focus of the research conducted in our group is the elucidation of how the signaling mechanisms initiated by the FcεRI, the FcγRI, Kit, and other receptors are utilized and integrated for the activation of mast cells. Activated mast cells release of a variety of inflammatory mediators, including histamine, arachidonic acid metabolites, and cytokines, which contribute to the initiation of the allergic reactions associated with asthma. Although the signaling cascades initiated by FcεRI, FcγRI and Kit share many common features, there are certain distinct differences in these pathways which significantly modify the resulting nature of mediator release upon receptor ligation/occupancy. Thus we are investigating common and distinct signaling events regulated by these receptors.
Recent studies have focused on the roles of PI-3 kinase, Btk, and the transmembrane adaptor molecules NTAL and LAT in these events. These studies have been conducted in human mast cells and mast cells derived from the bone marrow of knockout mice in combination with siRNA and shRNA approaches.
Major Areas of Research
- Cell biology of mast cells
- FcεRI-, FcγRI-, and Kit-regulated secretory responses
- Integration of signaling responses leading to mast cell activation
- PI-3 kinase and PLCγ1-mediated signaling events
- Trans-membrane adaptor molecules
Memberships
- American Society for Biochemistry and Molecular Biology
- Royal Pharmaceutical Society of Great Britain
Research Group Members
Shoko Iwaki, M.D., Ph.D.; Bettina M. Jensen, Ph.D.
Selected Recent Publications
To view a complete listing, visit PubMed.
Tkaczyk C, Beaven MA, Brachman SA, Metcalfe DD, Gilfillan AM. The PLCγ1-dependent pathways of FcεRI-mediated mast cell activation is regulated independently of PI-3 kinase. J Biol Chem. 2003. 278: 48474-48484.
Tkaczyk C, Horejsi V, Iwaki S, Draber P, Samelson L, Nahm DH, Metcalfe DD, Gilfillan AM. NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and FcεRI aggregation. Blood. 2004. 104: 207-214.
Hundley TR, Gilfillan AM, Tkaczyk C, Andrade MV, Metcalfe DD, Beaven MA. Kit and FcεRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood. 2004. 104: 2410-2417.
Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B. Essential role for the p110 phosphoinositide 3-kinase in the allergic response. Nature. 2004. 431: 1007-1011.
Iwaki S, Tkaczyk C, Satterthwaite AB, Halcomb K, Beaven MA, Metcalfe DD, Gilfillan AM. Btk plays a crucial role in the amplification of FcεRI-dependent mast cell activation by Kit. J Biol Chem. 2005. 280: 40261-40270.
Gilfillan AM, Tkaczyk C. Integrated signaling pathways for mast cell activation. Nature Reviews Immunology. 2006. 6: 218-230.
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