The Principal Investigator seeks advanced training in a mentored environment to study the contribution of the Receptor for Advanced Glycation Endproducts (RAGE) in tumor biology. The first objective is to provide an environment for the P.I., with her sponsor, Dr. David Stern, to obtain the needed training in formal courses and at the laboratory bench to develop into an independent clinician scientist. The second objective is to dissect the role of RAGE in modulating tumor cell properties. Recent studies indicated that expression of RAGE and one of its ligands, amphoterin, was markedly upregulated in the developing nervous system. In vitro, amphoterin-RAGE interaction mediated outgrowth of cerebral cortical neurites, as the process is inhibited by blocking antibodies to RAGE, or soluble RAGE (sRAGE), the extracellular ligand-binding domain of RAGE. These findings, along with the observation that enhanced levels of amphoterin and RAGE are present in tumors, suggested their possible contribution to tumor biology. In murine tumor models, blockade of amphoterin/RAGE suppressed activation of members of the MAP kinase family, p44/p42, p38 and SAPK/JNK, involved in tumor cell proliferation, invasion/migration, and activation of matrix metalloproteinases. In vivo, blockade of RAGE-amphoterin interaction suppressed primary tumors grown from implanted rat C6 glioma cells, and lung metastases in mice bearing Lewis lung carcinoma, by suppressing proliferation and invasiveness. In vitro, blockade of amphoterin-RAGE suppressed tumor cell proliferation, expression of cyclin D1, invasion and migration. We speculate that amphoterin-RAGE modulates critical properties within the tumor bed and hypothesize that subsequent to activation of tumor RAGE by ligand such as amphoterin, key cell signaling pathways are activated that contribute to tumor proliferation, invasion, migration and degradation of extracellular matrix. We propose two specific aims: 1. to delineate the signal transduction pathways activated upon engagement of RAGE, and 2. to determine if blockade of RAGE arrests progression of pre-malignant lesions. A range of tools will be employed in order to accomplish these goals, both in in vitro assay systems, and in vivo, using RAGE null mice and a murine model of familial adenomatous polyposis (FAP).
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