Signaling mechanisms for leukocyte migration regulation

Yale University, New Haven CT

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Directional cell migration, chemotaxis, has important roles in embryonic development, wound healing, tumor metastasis, and particularly various aspects of leukocyte biology including leukocyte infiltration, recruitment, trafficking, and homing These leukocyte processes are not only required for normal immune responses, but also responsible for many inflammation-related diseases including ischemic reperfusion, atherosclerosis, asthma, and sepsis. Our long term goal is to understand the signaling mechanisms by which chemoattractants regulate leukocyte chemotaxis and their roles in inflammation-related diseases models. Circulating naive neutrophils are apolar. Their adhesion to the endothelium and migration necessary for their infiltration into inflamed tissues require their polarization through a spatial reorganization of the cytoskeletal proteins, involving the formation of lamellar-type F actin at the front and the contractile actomyosin structure at the back. Although many signaling pathways have been characterized for regulating these polarization processes, a major gap that remains is how an apolar, naive neutrophil breaks its initial symmetry upon stimulation and knows where to form the single front and back in less than a minute. In the preliminary studies of this renewal application, we have characterized a novel directional vesicle transport mechanism and made observations that may provide the answer to this long-sought question how the symmetry of a naive neutrophil is broken initially. These preliminary results support a central hypothesis that the initial break of the symmetry may arise from cell attachment-induced polarization of a phosphatidylinositol lipid at the PM, which defines the back and thus the initial cellular polarity, upon which further polarization induced by chemo attractants is extended. In this renewal application, we will extend these ground-breaking preliminary results to complete the characterization of the aforementioned directional vesicle transport mechanism.