HomeResearchIntramural ResearchResearch Branches at NHGRIGenetic Disease Branch Schwartzberg Lab

Pamela L. Schwartzberg, M.D., Ph.D. Senior Investigator Genetic Disease Research Branch Head Cell Signaling Section B.A. Princeton University, 1981 M.D. Ph.D. Columbia University, 1992 (301) 435-1906 (301) 402-2170 pams@nhgri.nih.gov Building 49, Room 4A38 49 Convent Drive, MSC 4472 Bethesda, MD 20892-4472 Selected Publications

Our laboratory studies signal transduction pathways involving cytoplasmic tyrosine kinases, and how defects in these pathways contribute to disease processes. Through a combination of biochemical and genetic techniques, including the generation of transgenic and gene-targeted mice, we seek to determine the normal cellular functions of these molecules and how modulation of their action can lead to treatment for such diverse human diseases as immunodeficiencies, cancer, and osteoporosis. Our work concentrates on two families of tyrosine kinases, the Btk/Tec family and the Src family.

One of the major focuses of the laboratory is the study of molecules involved in signal transduction in T lymphocytes, and their impact on the proper development and regulation of immune cell function. To this end, we are studying members of the Btk/Tec family of tyrosine kinases expressed in T lymphocytes. X-linked agammaglobulinemia, an inherited B cell immunodeficiency disorder, results from mutated Btk. Recently, we discovered that the mutation of Itk and Rlk/Txk, Tec kinases expressed in T cells, can severely impair T lymphocyte function in mice. This study established a role for these kinases in T cell signaling for the first time. We are now investigating how alterations of these signaling pathways change lymphocyte development and responses to infection, with particular focus on the differentiation and function of CD4 T helper cell. We are also generating and analyzing gene-targeted mice with mutations in SAP, the gene responsible for X-linked lymphoproliferative disease, a disorder characterized by hyperactivation of the immune system due to a defect in a negative regulatory signaling molecule.

The other main focus of the laboratory is Src, a widely expressed tyrosine kinase that was first isolated as a proto-oncogene, and subsequently implicated in multiple signaling pathways in normal cells, including responses to growth factor and integrin adhesion receptors. In mice, mutation of Src results in an intrinsic defect in osteoclasts, the cells responsible for bone resorption, and causes osteopetrosis. Our research indicates that Src family kinases are essential for a novel signaling pathway that activates AKT downstream of RANK, a TNF receptor family member that is critical for osteoclast survival and function and that mediates bone destruction in animal models of rheumatoid arthritis. These studies have important consequences for the development of Src-based therapeutics for bone resorption diseases, such as osteoporosis and arthritis, and for treatment of tumors in which Src family kinases are activated.

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Last Reviewed: October 2004