Alasdair M. Gilfillan, Ph.D.

Assistant Section Chief

Dr. Gilfillan received his Ph.D. from the University of Manchester, U.K., and 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 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 is the elucidation of how the signaling mechanisms initiated by the FcεRI, Kit, and other receptors are used and integrated for mast-cell growth, development, and function. Mast cells develop from peripheral blood- and bone marrow-derived progenitor cells under the influence of critical cytokines, particularly SCF, the ligand for Kit. Once resident in their target tissues, mast cells can be activated to release a variety of inflammatory mediators, including histamine, eicosanoids, and cytokines, which contribute to the pathogenesis of the allergic reactions associated with asthma.

These events are initiatied following antigen-dependent aggregation of the high-affinity receptors for IgE (FcεRI) on the surface of the mast cell. These events can be dramatically potentiated by SCF and specific GPCR ligands. We are thus investigating how the signaling cascades initiated by these receptors may regulate mast-cell development and function in normal and disease states. In addition, we are attempting to identify polymorphisms in specific signaling molecules that may render mast cells hyperactive in specific conditions. Recent studies have focused on the roles of transmembrane adaptor molecules and PI3-Kinase regulated pathways in these responses. These studies have been conducted in human mast cells and mast cells derived from the bone marrow of knockout mice in combination with siRNA, shRNA, and transfection/transduction approaches.

Major Areas of Research

• Mast cell biology
• FcεRI-, Kit-, and GPCR-regulated secretory responses
• Integration of signaling responses leading to mast-cell growth, differentiation, and activation
• PI-3 kinase-regulated signaling pathways
• Transmembrane adaptor molecules
• Roles of signaling molecule polymorphisms in mast cell-related disease states

Memberships

• American Association of Immunologists
• American Society for Biochemistry and Molecular Biology
• Royal Pharmaceutical Society of Great Britain

Editorial Boards

• Journal of Immunology
• Immunology Letters
• The Open Immunology Journal
• The Open Allergy Journal

Research Group Members

From left, back row: Daniel Smrz, Ph.D.; Alasdair Gilfillan, Ph.D.; Tatsuki Kataoka, M.D.; Tomonobu Ito, M.D., Ph.D. Front row: Yun Bai, M.S.; Madeleine Radinger, Ph.D.; Hye Sun Kuehn, Ph.D.

Selected Recent Publications

To view a complete listing, visit PubMed.

Iwaki S, Tkaczyk C, Satterthwaite AB, Halcomb K, Beaven MA, Metcalfe DD, Gilfillan AM. Btk plays a crucial role in the amplification of FcεRI-mediated mast cell activation by Kit. J Biol Chem. 2005 Dec 2;280(48):40261-70.

Gilfillan AM, Tkaczyk C. Integrated signaling pathways for mast-cell activation. Nat Rev Immunol. 2006 Mar;6(3):218-30.

Jensen BM, Beaven MA, Iwaki S, Metcalfe DD, Gilfillan AM. Concurrent inhibition of Kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation. J Pharmacol Exp Ther. 2008 Jan;324(1):128-38.

Iwaki S, Spicka J, Tkaczyk C, Jensen BM, Furumoto Y, Charles N, Kovarova M, Rivera J, Horejsi V, Metcalfe DD, Gilfillan AM. Kit- and FcepsilonRI-induced differential phosphorylation of the transmembrane adaptor molecule, NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells. Cell Signal. 2008 Jan;20(1):195-205.

Kuehn HS, Beaven MA, Ma HT, Kim MS, Metcalfe DD, Gilfillan AM. Synergistic activation of phospholipases Cgamma and Cbeta: a novel mechanism for PI3K-independent enhancement of FcepsilonRI-induced mast cell mediator release. Cell Signal. 2008 Apr;20(4):625-36.

Kim MS, Kuehn HS, Metcalfe DD, Gilfillan AM. Activation and function of the mTORC1 pathway in mast cells. J Immunol. 2008 Apr 1;180(7):4586-95.

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