Clifford Lowell, MD, PhD

The Lowell laboratory studies tyrosine kinase and phosphatase 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, STIM2) 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 FcγRs) 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 cytoplasmic tyrosine phosphatases (mainly SHP1) in the counter regulation tyrosine kinases, especially in the setting of hematopoietic malignancy and inflammatory disease. Recent publications highlight the role of SHP1, as a negative regulator of anti-tumor immunity, as well as the role of integrin signaling adapter protein SKAP2 in human autoimmune disease, in particular type 1 diabetes. Publications total = 228; h-index 97.