Ann Richmond, Ph.D.

Research Summary

Research interests of the Richmond lab include transcriptional regulation of chemokines, the role of chemokines in chronic inflammatory conditions, angiogenesis, vascular disease and tumor progression, as well as signal transduction mechanisms involved in chemokine mediated chemotaxis. Work from the Richmond lab has shown that ligand mediated receptor desensitization and internalization are associated with cessation of burst of chemokine signaling mediated through the chemokine receptor, CXCR2, which is required for continuous response to a chemokine. Mutation of the receptor such that ligand no longer mediates internalization of the receptor is accompanied by prolonged response to ligand with regard to generation of IP3, calcium mobilization, and other intracellular signals. However, loss of receptor internalization is accompanied by a loss of chemotactic response, even though there is an increased length and strength of intracellular signals. Data to date suggest that it is the oscillation of signals that is required for a chemotactic response. Moreover, the activation signals need to localize at the leading edge or the uropod of the migrating cell. Current work is directed toward elucidating the specific CXCR2 and CXCR4 protein/protein interactions over a time course after ligand stimulation to characterize the ?chemosynapse?. Proteomics and two hybrid screen methodologies have been utilized to identify many of these protein/protein interactions and the functional significance of these interactions is being characterized in regard to effects on the organization of the actin cytoskeleton to mediate chemotactic responses. In addition the mechanism by which receptor internalization facilitates the establishment of an intracellular gradient of signals to establish polarity oscillations required for response to a chemotactic gradient is being characterized. State of the art techniques intravital confocal imaging, time lapse videomicroscopy, microfluidic gradient devices, transgenic and knock out animal models are being used to explore the significance of these chemokine receptor/protein interactions in vascular development, angiogenesis and in breast cancer metastasis. Other projects in the laboratory are focused on the disregulation of NF-kB and its link between inflammation, angiogenesis and cancer. Constitutive activation of NF-kB is characteristic of many cancers and this is associated with over-expression of inflammatory cytokines and chemokines which set up a microenvironment that facilitates angiogenesis and tumor progression. Translational studies ongoing in the laboratory aim to examine the effectiveness of inhibitors of the NF-kB pathway as therapy for cancers.