The Lowell laboratory studies tyrosine kinase based signal transduction in innate immune cells. Our general approach involves examination of innate immune function in knockout mice lacking various members of the Src-family or Syk family of tyrosine kinases. Many of these studies also involve use of mice lacking these kinases in specific hematopoietic lineages, such as neutrophils, macrophages or DCs, generated through Cre/Lox technology. We have also used this approach to study other tyrosine kinases (Pyk2/Fak) and intracellular signaling molecules (WASp, STIM1) in innate immune cells. Our major findings have illuminated the function of Src-family and Syk kinases in leukocyte integrin signaling – loss of these kinases results in significant defects in inflammatory and host defense functions mediated by integrins. We have found that leukocyte integrin signaling utilizes the same intracellular pathways initiated by classical immunoreceptors (such as Fc?Rs) by co-opting ITAM-containing adapter proteins. We have also demonstrated the important ways these kinases regulate innate immune cells in the setting of autoimmune and inflammatory diseases, using the Lyn kinase-deficient model. Ongoing studies also involve examination of tyrosine phosphatases (mainly SHP-1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy, as well as studies of calcium signaling proteins, using mice lacking these genes specifically in myeloid lineage cells. Publications total = 191