Clifford Lowell, MD, PhD

Affiliated

My research group studies the role of the Src-family and Syk tyrosine kinase in signal transduction pathways within hematopoietic cells. These proteins play critical roles in transducing signals from cell surface receptors to intracellular targets. The diversity of signaling pathways in which these kinases have been implicated is very large, ranging from responses to innate immune stimuli (bacterial/viral products) to regulation of proliferative responses to cytokines or growth factors. We have taken a genetic approach to study these kinases by generating mutant mice (using embryonic stem cell technology) that lack Src-kinases, Hck, Fgr, and Lyn or Syk, then studying primary hematopoietic cells from these animals.

Our major finding has been that these kinases function in signaling pathways initiated by integrin-mediated cell adhesion. Integrins are heterodimeric cell surface proteins that mediate attachment of all cells to extracellular matrix protein (i.e., collagen, fibrinogen or fibronectin) coated surfaces; in vivo, these receptors control leukocyte migration and activation. Paradoxically, some of these kinases function in an inhibitory role to downmodulate, in particular, chemokine and other G-protein receptor signaling pathways. These kinases also directly function in hematopoietic stem cells, to regulate stem cell homing and responsiveness to cytokine growth factors. Ultimately, these studies will provide a better molecular understanding of leukocyte signal transduction, with the hope that therapeutic manipulation of these pathways can be achieved for the treatment of inflammatory, autoimmune and malignant disease.