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Department of Pediatrics The Rawlings lab is currently accepting new graduate students. Dr. Rawlings graduated Magna Cum Laude in Biological Sciences from Davidson College, and received his MD from the University of North Carolina. He completed residency and chief residency in pediatrics at UCSF, and Pediatric Rheumatology/Immunology subspecialty training at Children's Hospital Los Angeles. He pursued post-doctoral research as an Intramural fellow at the NIH and in the HHMI, UCLA. Formerly a member of the UCLA faculty, Dr. Rawlings joined the University of Washington as the Head, Section of Pediatric Immunology in 2001, and now directs the Research Center for Immunity and Immunotherapies at the Seattle Children’s Hospital Research Institute. The Rawlings laboratory uses expertise in basic and clinical immunology, signal transduction, and lymphocyte developmental biology to understand how altered signals can lead to immunologic diseases. This work is relevant to a range of related outcomes because dysregulation of lymphocyte growth and differentiation can lead, alternatively, to immunodeficiency states, or to autoimmunity and malignancy. Ultimately, we seek to utilize this information to develop translational therapies capable of specifically modulating these disorders. Current project areas include: I). Lymphocyte signal transduction. B cell antigen receptor (BCR) engagement generates a multi-component complex of signaling effectors, or "signalosome", that simultaneously trigger both positive and negative signals. The response to receptor engagement depends on the convergence of these signals. Two critical signals regulated by this "signalosome" include: a.) the sustained intracellular calcium signal; and b.) activation of NFκB-mediated survival signals. Our work has focused on the biochemical events regulating these signals. Our current studies include biochemical analysis of tyrosine kinases, adapter proteins, and lipid enzymes; and use of various animal models to evaluate the developmental consequences of altered expression of these proteins. II). Gene Therapy for primary immunodeficiency disorders. The past decade has witnessed tremendous progress in linking deficient function of signaling effectors with specific primary immunodeficiency disorders (PIDD). The non-receptor tyrosine kinase, Btk, is mutated in the primary B lineage immunodeficiency disease X-linked agammaglobulinemia (XLA in humans and in X-linked immunodeficiency, XID in mice). Similarly, mutation of the Wiskott-Aldrich Syndrome protein (WASp) leads to a multilineage immunodeficiency in humans and mice. Because of the selective advantage for gene corrected cells, these disorders represent excellent targets for stem cell-based gene therapy. We have developed lineage specific viral systems for use in hematopoietic stem cells. We are also evaluating the capacity of Homing endonucleases (HEs) to facilitate genetic repair of the mutant loci in animal models of immunodeficiency. Our ongoing includes analysis of reconstitution function in mutant mice, and human multipotent stem cells in vitro and in vivo. The laboratory is strongly committed to moving from preclinical studies into translational trials of clinical gene therapy for patients with primary immunodeficiency disorders. III). Modeling normal and altered lymphopoiesis. We have developed unique (human and murine) in vitro B lineage culture models. These systems aid in identifying the signals that regulate B lymphopoiesis and B cell activation. We are utilizing these in vitro models, in conjunction with animal-based approaches (transgenic, knockout, and RNA interference) to model B lineage development and B lymphoid malignancies. Current studies include analysis of Thymic stromal lymphopoeitin-receptor (TSLP), Toll, Notch, and BAFF-receptor signaling cascades in the generation of peripheral B cell subsets; and analysis of the PKCβ/NFκB pathways in the development or progression of lymphoma. Students currently training in the Rawlings lab include: Sarah Andrews, Ashok Bandaranayake, Alexander Astrakhan. I) Representative publications on "Lymphocyte signal transduction" include: Scharenberg AM, Humphries LA, and Rawlings DJ. Calcium signalling and cell-fate choice in B cells. (2007) Nat Rev Immunol (In Press). Rawlings DJ, Sommer K, Moreno- García ME. The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. (2006) Nat Rev Immunol 6(11):799-812. Gomez TS, McCarney SD, Carrizosa E, Labno CM, Comiskey EO, Nolz JC, Zhu P, Freedman BD, Clark MR, Rawlings DJ, Billadeau DD, Burkhardt JK. HS1 Functions as an Essential Actin-Regulatory Adapter Protein at the Immune Synapse. (2006) Immunity 24:1-12. Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, Rawlings DJ. Phosphorylation of the CARMA1 Linker Controls NF-κB Activation. (2005). Immunity 23(6): 561-574. Humphries LA, Dangelmaier C, Kato RM, Griffith N, Irene Bakman I, Christoph W. Turk CW, Daniel JL, Rawlings DJ. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the PLCg SH2-SH3 linker. (2004) J Biol Chem 279(36):37651-37661. Rawlings DJ. The biology and biochemistry of inflammatory signolosomes. (2006) EMBO Reports 7 (1): 25-30. Guo B, Su TT, Rawlings DJ. PKC family functions in B cell activation. (2004) Curr Opin Immunol 16(3):367-373. Saito K, Tolias KF, Saci A, Koon HB, Humphries LA, Scharenberg A, Rawlings DJ, Kinet J-P, Carpenter CL. Btk regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity. (2003) Immunity 19:669-678. Su TT, Guo B, Chae K, Kawakami Y, Chae K, Kato RM, Kang SW, Patrone L, Wall R, Teitell MA, Leitges M, Kawakami T, Rawlings DJ. PKCb controls IkB kinase (IKK) lipid raft recruitment and activation in response to BCR signaling. (2002) Nature Immunol 3:780-786. Kang, SW, Wahl, MI, Leitges M, Tarakhovsky, A, Tabuchi, R, Kato,R, Turck, CW, Kawakami, T, Witte ON, Rawlings, DJ PKCb modulates antigen receptor signaling via regulation of Btk membrane localization. (2001) EMBO 20:5692-5702. Guo B, Kato RM, Garcia-Lloret M, Wall M and Rawlings DJ: Engagement of the human pre-B cell receptor (pre-B) generates a lipid raft-dependent calcium signaling complex. (2000) Immunity 13:243-253. Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger A-C, Witte ON, Kinet J-P: Activation of Btk by a phosphorylation mechanism initiated by src family kinases. (1996) Science 271:822-825. Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG, Jenkins NA and Witte ON: Mutation of the BPK tyrosine kinase unique region in X-linked immunodeficiency. (1993) Science 261:358-361. II) Representative publications on "Gene therapy for primary immunodeficiency disorders" include: Miao, CH, Ye, P, Thompson, AR, Rawlings, DJ, Ochs, HD. Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice. (2006) Blood 108(1):19-27. Yu PW, Tabuchi RS, Kato RM, Astrakhan A, Chae K, Ellmeier W, Witte ON, Rawlings DJ. Sustained correction of B cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral gene transfer. (2004) Blood 104(5):1281-1290. Humblet-Baron S, Anover S, Kipp K, Zhu Q, Ye P, Zhang W, Ovechkina Y, Khim S, Astrakhan A, Strom T, Kohn D, Candotti F, Vyas Y, Ochs H, Miao C, Rawlings D. Lentiviral vector-mediated gene therapy as treatment for Wiskott-Aldrich Syndrome (WAS): Pre-clinical studies in human cell lines and WASp -/- mice. (2005) Molecular Therapy 11(1):S133. Scharenberg AM, Rawlings DJ, Monnat RJ, Stoddard BL. Engineering and development of I-AniI homing endonucleases for gene correction applications. (2005) Molecular Therapy 11(1): S405. Rawlings DJ. Bruton's tyrosine kinase controls a sustained calcium signal essential for B lineage development and function. (1999) Clinical Immunology 91:243-254. III) Representative publications on "Modeling normal and altered lymphopoiesis" include: Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, Mauri C. Novel suppressive function of transitional 2 B cells in experimental arthritis. (2007) J Immunol 178(12):7868-7878. Humblet-Baron S, Sather B, Anover S, Becker-Herman S, Kasprowicz DJ, Khim S, Nguyen T, Hudkins-Loya K, Alpers CE, Ziegler SF, Ochs H, Torgerson T, Campbell DJ, Rawlings DJ. Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. (2007) J Clin Invest. 1;117(2):407-418. Astrakhan A, Omori M, Nguyen T, Becker-Herman S, Iseki M, Aye T, Hudkins-Loya K, Dooley J, Farr A, Alpers CE, Ziegler S, and Rawlings DJ. Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell. (2007) Nature Immunology 8(5):522-531. Su TT, Guo B, Wei B, Braun JB, Rawlings DJ. Signaling of transitional type 2 B cells is critical for peripheral B cell development. (2004) Immun Rev 197:167-178. Hoyer KK, French SW, Turner DE, Nguyen MTN, Renard M, Malone CS, Knoetig S, Qi CF. Su TT, Cheroutre H, Wall R, Rawlings DJ, Morse HC, and Teitell MA. Dysregulated TCL1 Promotes multiple classes of mature B cell lymphoma. (2002) Proc Nat Acad Sci USA 99: 14392-14397. Su TT, Rawlings DJ. Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. (2002) J. Immunol. 168: 2101-2110.
COS expertise
profile Updated 8/29/07
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