David J. Rawlings, MD
Children's Guild Association Endowed Chair in Pediatric Immunology
Director, Center for Immunity and Immunotherapies
Seattle Children's Research Institute
Chief, Division of Immunology
Seattle Children's Hospital
Adjunct Professor, Immunology
University of Washington School of Medicine
Seattle Children's Research Institute
1900 9th Avenue
Seattle, WA 98101
Tel: (206) 987-7450
Dr. Rawlings is Professor of Pediatrics and Immunology at the University of Washington and Head, Section of Immunology, at Seattle Children's Hospital. He is internationally recognized for his work in B-cell development and signal transduction, and has ongoing projects in B-cell signaling, development and application of lentiviral vectors for gene therapy of the primary immunodeficiencies XLA and WAS, and applications of lentiviral vectors for gene repair in hematopoietic stem cells.
Dr. Rawlings is co-director of the NGEC and a principal investigator in the area of gene repair in murine immunodeficiency models.
Awards and Honors
- University of North Carolina Merit Scholarship: 1981
- Sarah Graham Kenan Scholarship: 1983
- Diplomate, American Board of Pediatrics: 1988
- Merle Carson Research Award (First Place), Southwestern Pediatric Society: 1992
- Beatrice S. Kolliner Memorial Fund Fellow, Jonsson Cancer Center: 1993
- Ellis Dresner Research Award (First Place), Southern California Rheumatology Society: 1993
- Physician Scientist Award, NIDDK, NIH: 1993 - 1998
- Diplomate, American Board of Pediatric Rheumatology: 1994
- Lupus Foundation Award: 1996-1998
- James S. McDonnell Scholar: 1997-2000
- CHRC/HHMI/Pennington Research Awards, UCLA: 1996-1998
- Joan J. Drake Seed Grant for Excellence in Cancer Research, 1998
- Scholar Award, The Leukemia and Lymphoma Society: 1999-2004
- Member, American Society for Clinical Investigation: 2001–present
- Member, Association of American Physicians: 2007–present
Areas of Expertise
- Basic and clinical immunology
- Signal transduction
- Lymphocyte developmental biology
- Lymphocyte signal transduction
- Gene therapy for primary immunodeficiency disorders
- Modeling normal and altered lymphopoiesis
Overview of the Rawlings Lab
The Rawlings Lab 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, Dr. Rawlings and his team seek to utilize this information to develop translational therapies capable of specifically modulating these disorders.
As a postdoctoral fellow in Dr. Owen Witte’s laboratory, Dr. Rawlings initially characterized the role of Bruton’s tyrosine kinase (Btk) in B-cell development and how deficient function of this enzyme led to the related immune disorders X-linked immunodeficiency (XID; in mice) and X-linked agammaglobulinemia (XLA; in humans). Subsequently, his laboratory has worked to define the molecular events that link Btk to B-cell receptor signaling.
His group identified the downstream requirement for Btk in calcium signaling via activation of phosholipase C gamma (PLCγ), and in the NFκB cascade through protein kinase C-beta (PKCβ) and the adapter protein, CARMA1. In parallel, his laboratory has pioneered studies demonstrating rescue of B cell development in animal models of XLA using viral vectors for <span class=">gene therapy and is working to move this approach into clinical trials.
For its role in the NGEC, the Rawlings Lab will utilize two murine immunodeficiency disorders as model systems to evaluate methods for delivery of an LHE and donor template to induce gene repair in hematopoietic stem cells. In both models, a selective advantage for gene-corrected lymphoid stem cells will provide a useful initial system in which to evaluate both feasibility and efficiency of various repair strategies.
In collaboration with the Scharenberg Lab, Dr. Rawlings and his team have generated a novel murine model of X-linked severe combined immunodeficiency (XSCID) will enable the lab to evaluate gene repair under near ideal conditions using the well-characterized LHE, I-SceI. This model will allow the Rawlings Lab to evaluate a range of NIL vector designs, transduction protocols and HSC target populations in order to identify optimal methods for in vivo gene repair.
Following establishment of successful gene repair, the Rawlings Lab will then utilize the identical LHE-XSCID animal model and delivery systems to evaluate the functional activity of an engineered I-AniI enzyme.
Subsequently, the lab will evaluate a second engineered LHE, designed to cut within the Btk gene at the X-linked immunodeficiency (XID) locus. NIL vectors, carrying the XID-specific LHE and a repair template with or without a cis-linked selection marker, will be used to determine if drug selection can enrich gene repaired stem cells and, thereby, enhance the rate of immune reconstitution in this animal model.
The combined studies of the Rawlings Lab will provide a key benchmark against which to judge gene repair approaches using engineered LHEs and NIL delivery systems..
Key personnel carrying out this research include Elle Curinga (postdoctoral fellow), Yupeng Wang (postdoctoral fellow), and Kamila Gwiazda (graduate student).