Training:
• Ph.D., 1979, University of Chicago
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M.D., 1981, University of Chicago
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Residency, 1981-1985, Pediatrics, University of California, San Francisco, CA
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Fellowship, 1865-1988, Pediatric Hematology/Oncology, Harvard Medical
School, The Children's Hospital and Dana Farber Cancer Institute,
Laboratory of Stuart Orkin Description and summary of research focus of the laboratory:
Dr. Dinauer's laboratory interests include characterization of the phagocyte respiratory burst oxidase and its role in human disease as well as gene therapy of inherited hematopoietic disorders. Genetic defects in the superoxide-generating phagocyte respiratory burst oxidase result in chronic granulomatous disease (CGD), a recessive inherited disorder characterized by an absent respiratory burst and recurrent, often life-threatening infections. While superoxide is essential for normal host defense, the excessive or inappropriate release of oxidants also contributes to tissue injury in a variety of inflammatory disease states. The active oxidase complex is formed from both soluble proteins and a membrane-bound, low-potential flavocytochrome b, and requires Rac GTPase for full activity. A major emphasis of Dr. Dinauer's work has involved flavocytochrome b, a heterodimer comprised of a 91 kDa membrane glycoprotein encoded by a gene at Xp21, and a 22 kDa peptide derived from an autosomal gene at 16q24. This phagocyte-specific flavocytochrome functions as the electron carrier in the oxidase complex and is the focal point for oxidase assembly at the plasma membrane when phagocytes are activated by inflammatory stimuli. Ongoing projects include: 1) Characterization of functional domains involved in assembly and enzymatic activity of the oxidase complex and the role of Rac GTPases in this process . Approaches include site-directed mutagenesis and expression of recombinant oxidase subunits in cell lines. The role of small GTPases in phagocyte signal transduction pathways that activate other functional processes, such as phagocytosis or chemotaxis is also under investigation. This question is being approached using expression of dominant-negative and activated forms of the proteins as well as gene targeting technologies. 2) Analysis of inflammation and infection in murine X-linked CGD. This model is being applied to evaluate the role of phagocyte-derived oxidants in the inflammatory response and in host defense. 3) Gene replacement therapy of X-linked CGD. These studies involve the use of viral vectors for transduction of human and murine hematopoietic cells derived from bone marrow, peripheral blood, and cord blood. The application of these vectors and development of transplantation regimens for gene therapy of X-CGD is being studied in the X-CGD mouse and in patients with X-CGD, both in pre-clinical studies and in Phase I clinical trials. Publications
Dinauer, M.C., Gifford, M.A., Pech, N., Li, L.L., Emshwiller, P. 2001.Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease. Blood 97: 3738-3745. Li, S., Yamauchi, A., Marchal, C.C., Molitoris, J.K., Quilliam, L.A., Dinauer,M.C.,. 2002. Chemoattractant-stimulated Rac activation in wild type and Rac2-deficient murine neutrophils: Preferential activation of Rac2 and Rac2 gene dosage effect on neutrophil functions. J Immunol 169:5043-5051. Price, M.O., Atkinson, S.J., Knaus, U.G., Dinauer, M.C.,. 2002. Rac activation induces NADPH oxidase activity in transgenic COSphox cells and level of superoxide production is exchange factor-dependent. J Biol Chem. 277:19220-19228. Price, M.O., McPhail, L., Lambeth, J.D., Knaus, U., Dinauer,M.C.,. 2002. Creation of a genetic system for analysis of the phagocyte respiratory burst: high-level reconstitution of the NADPH oxidase in a nonhematopoietic system. Blood. 99:2653-2661. (Plenary Paper) Sadat, MA, N Pech, SO Saulnier, BA LeRoy, JP Hossle, M Grez, MC Dinauer . 2003. Long term high-level reconstitution of NADPH oxidase activity in murine X-CGD using a bicistronic vector expressing gp91 phox and D LNGFR cell surface marker. Hum Gene Ther 14:651-666. Search Pub Med Return to Homepage |
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