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Ann Richmond, Ph.D.

Professor of Cancer Biology and Medicine
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
432-B Preston Building
Nashville, TN 37232-6840
615-343-7777

Profile

Ann Richmond, Ph.D. is a Professor in the Department of Cancer Biology at Vanderbilt University School of Medicine. Her research interests include transcriptional regulation of chemokines, the role of chemokines in chronic inflammatory conditions, wound healing and tumor progression, as well as signal transduction mechanisms involved in chemokine mediated chemotaxis.
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Ann Richmond, Ph.D. is a Professor in the Department of Cancer Biology at Vanderbilt University School of Medicine. Her research interests include transcriptional regulation of chemokines, the role of chemokines in chronic inflammatory conditions, wound healing and tumor progression, as well as signal transduction mechanisms involved in chemokine mediated chemotaxis. Her laboratory has extensively studied the factors contributing to the constitutive transcription of angiogenic chemokines during tumor progression. They are currently testing the utility of targeting the transcription factor, NF-kB, as a therapeutic approach for treatment of malignant melanoma. Work from her lab has also elucidated the role of ligand mediated receptor phosphorylation in the facilitation of chemokine receptor desensitization. Moreover, her research team has shown that ligand mediated receptor internalization is 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 the chemotactic response, even through 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. Using state of the art microfluid devices, time lapse video microscopy, FRET analysis of localized activation of Rac-1, Cdc42 and Rho GTPases, Richmond's research group is characterizing the mechanism by which altered adaptor binding to chemokine receptors or altered internalization of receptors alters the chemotactic response. Ongoing research is aimed at examination of 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 with the end result leading to a better understanding of how chemokines mediate cancer cell metastasis as well as chronic inflammatory conditions.

Research Description

Her research interests include transcriptional regulation of chemokines, the role of chemokines in chronic inflammatory conditions 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 internalization is associated with oscillations of intracellular signaling 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. However, loss of receptor internalization is often accompanied by a loss of chemotactic response, even though there is an increased length and strength of intracellular signals. Current work is directed toward illucidating the specific CXCR2 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 interaction 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 breast cancer. Other projects in the laboratory are focused on the disregulation of NF-kB and its link between inflammation 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 tumor progression. Translational studies are ongoing to determine how disruption of NF-kB or specific chemokine receptors affects the leukocytic infiltrate of the tumor microenvironment, tumor progression and metastisis.

Publications


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