Mary C. Dinauer, M.D., Ph.D.
Nora Letzter Professor: Department of Pediatrics
Director: Herman B Wells Center for Pediatric Research
Associate Chair for Basic Research: Department of Pediatrics
Clinical Section: Pediatric Hematology/Oncology
Basic Science Joint Appointments: Microbiology and Immunology, Medical and Molecular Genetics
Fellowship: Pediatric Hematology/Oncology, Harvard Medical School,The Children's Hospital and Dana Farber Cancer Institute
Residency: University of California, San Francisco, CA
M.D.: University of Chicago, 1981
Ph.D.: University of Chicago, 1979
Current Research Interests:
Characterization of the phagocyte respiratory burst oxidase and its role in human disease, gene therapy of inherited hematopoietic disorders.
Research:
Genetic defects in the phagocyte respiratory burst oxidase pathway that generates superoxide 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 cytochrome b, and requires GTP and one or more small GTPases for full activity. The major emphasis of our work thus far has involved the cytochrome, 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 cytochrome 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. We are also interested in the role of small GTPases in phagocyte signal transduction pathways that activate other functional processes, such as phagocytosis or chemotaxis. These questions are being approached using a combination of molecular and cell biology approaches using cell lines and mice generated by gene targeting.
2) Analysis of inflammation and infection in murine X-linked CGD. We have used gene targeting in murine embryonic stem cells to develop a mouse model of X-linked CGD. This model is being used 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.
