Mechanisms of Regulating Cell Migration

Washington University, Saint Louis MO

Investigators

Abstract

DESCRIPTION (provided by applicant): Cell migration plays important roles in multiple physiological and pathological processes. Both insufficient or excessive cell migration has been implicated in pathogenesis of human diseases. Activation o chemokine-induced chemotaxis has been associated with a number of inflammatory disorders. Our understanding of regulation of cell migration by endogenous factors has been limited, in particular in the area of negative regulation of leukocyte movement. Our previous studies have identified a protein slit, that has chemorepellent activity on neurons in the mammalian nervous system. Our preliminary study has shown that Slit can inhibit chemokine-induced migration of leukocytes and attenuate experimental glomerulonephritis in an animal model. These results led us to propose to investigate the potential role of Slit in modulating inflammatory responses. We have established in vitro cell migration assays using both neuronal cells and leukocytes. We have begun to use animal models to examine effects of Slit in regulating cell migration. Systematically investigating both spectrum and specificity of Slit effect on leukocyte migration induced by different chemokines an dissecting signal transduction pathways involved in chemotaxis inhibition will help understanding molecular mechanisms underlying the regulation of cell migration. Studying the effect of Slit in animal models will help in assessing the potential in developing Slit derivatives of therapeutic value for treating inflammatory diseases. A comparison of the cell migration in the nervous and immune systems will help understand both systems and may shed light on common mechanisms of cell migration.