Program Description
The primary focus of the research is the elucidation of how the signaling mechanisms initiated by the high affinity receptor for IgE (FcεRI), the growth factor receptor Kit, and other receptors are used and integrated for mast-cell growth, development, and function. Mast cells develop from bone marrow-derived progenitor cells under the influence of critical cytokines, particularly stem cell factor (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 anaphylaxis, asthma, and other allergic disorders.
These events are generally initiated following antigen-dependent aggregation of the FcεRI on the surface of the mast cell. These events, however, 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 mast cell-driven disorders. Finally, we are examining how mast cells can be reprogrammed in health and disease to alter the activation phenotype. 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.
Biography
Dr. Gilfillan received his Ph.D. from the University of Manchester, United Kingdom, 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.
Memberships
- American Association of Immunologists
- American Society for Biochemistry and Molecular Biology
Editorial Boards
- World Journal of Biological Chemistry (2010- )
- Journal of Immunology (2008- )
- Immunology Letters (2007- )
- The Open Immunology Journal (2007- )
- The Open Allergy Journal (2007- )
- Journal of Pharmacology and Experimental Therapeutics (1994-2001)
Research Group
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 Publications
Gilfillan AM, Beaven MA. Regulation of mast cell responses in health and disease. Crit Rev Immunol. 2011;31(6):475-529.
Smrz D, Kim MS, Zhang S, Mock BA, Smrzová S, DuBois W, Simakova O, Maric I, Wilson TM, Metcalfe DD, Gilfillan AM. mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood. 2011 Dec 22;118(26):6803-13.
Rådinger M, Smrž D, Metcalfe DD, Gilfillan AM. Glycogen synthase kinase-3β is a prosurvival signal for the maintenance of human mast cell homeostasis. J Immunol. 2011 Dec 1;187(11):5587-95.
Kuehn HS, Jung MY, Beaven MA, Metcalfe DD, Gilfillan AM. Prostaglandin E2 activates and utilizes mTORC2 as a central signaling locus for the regulation of mast cell chemotaxis and mediator release. J Biol Chem. 2011 Jan 7;286(1):381-402.
Gilfillan AM, Metcalfe DD, editors. Mast cell biology: contemporary and emerging topics. Austin, TX: Landes Bioscience; 2011.
Kuehn HS, Rådinger M, Brown JM, Ali K, Vanhaesebroeck B, Beaven MA, Metcalfe DD, Gilfillan AM. Btk-dependent Rac activation and actin rearrangement following FceRI aggregation promotes enhanced chemotactic responses. J Cell Sci. 2010 Aug 1;123(Pt 15):2576-85.
Visit PubMed for a complete publication listing.
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