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David J. Rawlings, M.D.
David J. Rawlings, M.D.
Professor, Pediatrics; Director, Center for Immunity and Immunotherapies, Seattle Children's Research Institute; Chief, Division of Immunology, Seattle Children's Hospital; and Adjunct Professor, Immunology
Dr. Rawlings graduated Magna Cum Laude in Biological Sciences from Davidson College, and received his M.D. 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 in 2001. He directs the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute and is also chief of the Division of Immunology overseeing the immunodeficiency clinic at Seattle Children’s Hospital. Dr. Rawlings has received numerous awards and was elected to the American Society for Clinical Investigation in 2001 and the Association of American Physicians in 2007.
Department of Pediatrics
University of Washington
Center for Immunity and Immunotherapies
Seattle Children's Research Institute Box 359300 JMB-6
1900 9th Avenue
Seattle WA 98101
Dr. Rawlings’ primary research interests include dysregulated B cell development and signaling leading to immunodeficiency, autoimmunity or lymphoid malignancies, and the development of gene therapy for primary immune deficiency diseases. His laboratory uses expertise in basic and clinical immunology, signal transduction and lymphocyte developmental biology to understand how altered signals can lead to immunologic disease, with the ultimate goal of developing translational therapies capable of specifically modulating these disorders. Dr. Rawlings is a member of multiple regional and national organizations, an NIH study section member, and ad hoc reviewer for various grant programs and immunology journals. He also co-directs the Northwest Genome Engineering Consortium, a research program funded as part of the NIH Roadmap for Medical Research focused on developing enzymatic reagents and delivery methods for site specific gene repair in hematopoietic stem cells.
1). 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.
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 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.
Modeling normal and altered lymphopoiesis. We utilize unique (human and murine) in vitro B lineage culture models and murine knock-in /knock out models to study the signals that regulate B lymphopoiesis, B cell activation and B lineage Function in autoimmunity and malignancies. Current studies include analysis of Toll like receptor, Notch, and BAFF-receptor signaling cascades in the generation of peripheral B cell subsets and B cell tolerance; and analysis of the PKCβ/NFκB/PKD pathways in the development or progression of lymphoma.
Representative recent publications:
1. Krishnamurty AT, Thouvenel CD, Portugal S, Keitany GJ, Kim KS, Holder A, Compton PD, Rawlings DJ, Pepper M. Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge. Immunity. 2016 PMID:27473412
2. Hale M, Mesojednik T, Romano Ibarra GS, Sahni J, Bernard A, Sommer K, Scharenberg, AM Rawlings DJ, Wagner TA. Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol Ther. 2016 PMID:28143740
3. Jacobs HM, Thouvenel CD, Leach S, Arkatkar T, Metzler G, Scharping NE, Kolhatkar NS, Rawlings DJ, Jackson SW. Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells. J Immunol. 2016 PMID:4868625
4. Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, Ochs HD, Rawlings DJ, Scharenberg AM, Torgerson TR. Targeted Gene Editing Restores Regulated CD40L Expression and Function of X-HIGM T Cells. Blood. 2016 PMID:26903548
5. Jackson SW, Jacobs HM, Arkatkar T, Dam E, Scharping NE, Kolhatkar NS, Hou B, Buckner J, Rawlings DJ. B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J Exp Med. 2016 PMID:4854732
6. Sather BD, Romano Ibarra GS, Sommer K, Curinga G, Hale M, Khan I, Singh S, Song Y, Gwiazda KS, Sahni J, Jarjour J, Astrakhan A, Wagner TA, Scharenberg AM, Rawlings DJ. Efficient Modification of CCR5 in Primary Human Hematopoietic Cells using a megaTAL Nuclease and AAV Donor Template. Sci Trans Med. 2015 PMID:34790757
7. Kolhatkar NS, Brahmandam A, Thouvenel CD, Becker-Herman S, Jacobs HM, Schwartz MA, Allenspach EJ, Khim S, Panigrahi AK, Luning Prak ET, Thrasher AJ, Notarangelo LD, Candotti F, Torgerson TR, Sanz I, Rawlings DJ. Altered BCR and TLR Signals Promote Enhanced Positive Selection of Autoreactive Transitional B cells in Wiskott-Aldrich Syndrome. J Exp Med. 2015 PMID:4577851
8. Dai X, James RG, Habib T, Singh S, Jackson SW, Khim S, Moon RT, Liggitt D, Wolf-Yadlin A, Buckner JH, Rawlings DJ. A Disease-associated PTPN22 Variant Promotes Systemic Autoimmunity in Murine Models. J Clin Invest. 2013 PMID:3638909
9. Hale M, Lee B, Honaker Y, Leung WH, Grier AE, Jacobs HM, Sommer K, Sahni J, Jackson SW, Scharenberg AM, Rawlings DJ. Homology-Directed Recombination for Enhanced Engineering of Chimeric Antigen Receptor T cells. Mol Ther – Meth Clin Dev. 2017
10. Singh S, Khan I, Khim S, Seymour B, Sommer K, Wielgosz M, Norgaard Z, Kiem HP, Adair J, Liggitt D, Nienhuis A, Rawlings DJ. Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector. Mol Ther – Meth Clin Dev. 2017
B.S., Biological Sciences, Davidson College
M.D., University of North Carolina
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