Microbiology, Molecular Genetics and Immunology
Ph.D., Harvard University, Boston, 1997
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Office: 3010 Hixon | Lab: 3001/3012 Hixon
913-588-7088 | email
Our research centers on understanding the regulation of trafficking and cellular signaling events, which occur in response to stimulation of the CCR7 G-protein coupled receptor (GPCR). This receptor is normally expressed on progenitor T-cells (precursors for childhood T-ALL), B-cells and mature dendritic cells, where it serves as the major homing receptor for localization to secondary lymphoid organs. In addition, during development this receptor functions to organize and maintain the architecture of the spleen, lymph nodes, thymus and Peyers's patches of the small intestine. These organs play critical roles in the immune system, metastatic cancer and in leukemogenesis. CCR7 expression is up-regulated in metastatic melanoma, breast cancer, prostate cancers, certain leukemias and in Hodgkin's lymphoma. The consequence of up-regulation in these diseases remains unclear, but is likely to result in targeting cells to lymphoid organs to enhance cellular proliferation.
To control targeting and potential cellular proliferation mediated by the CCR7 receptor, it is important to understand how the receptor is regulated. However, it is unclear how activated GPCRs are regulated/desensitized. As more GPCRs are characterized it becomes apparent that trafficking and desensitization of GPCRs is diverse. For instance, the well characterized, beta-2 adrenergic receptor is down-regulated and internalized via clathrin coated pits and requires cytoplasmic arrestins to internalize. Like the beta-2 receptor, the beta-1 adrenergic receptor is internalized through clathrin coated pits via arrestins, but is found on endosomes distinct from the beta-2 receptor following internalization. In contrast, we have shown that the N-formyl peptide receptor does not require arrestins or clathrin for internalization, and appears to use a third endosomal pathway. Receptor desensitization is a critical element of receptor regulation that prevents over stimulation of cells. This over stimulation can have deleterious consequences, such as reperfusion injury with the N-formyl peptide receptor. Therefore, it is extremely important to characterize the trafficking/regulation of GPCRs, in this instance the CCR7 receptor, to better understand its role in metastatic cancer, Hodgkin's lymphoma and leukemia.
Since GPCRs are the target of ~40% of the drugs currently on the market, it is surprising how little is known of the regulation of the trafficking/signaling from the CCR7 receptor, in particular how the receptor is down regulated following stimulation. This knowledge will provide researchers with tools for developing therapeutic approaches for inhibiting CCR7 mediated disease processes. For instance, recent studies by our laboratory have demonstrated a role for GPCRs in the regulation of cell survival/apoptosis in response to ligand binding. How the CCR7 receptor is regulated, and the effects of this regulation on cell survival and migration is the focus of our current research.
Charlotte M. Vines, Ph.D.