Macrophage and Microglial Activation in Glioma-Associated Inflammation

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The goal of this project is to provide the applicant, Nalin Gupta, with the necessary expertise to develop an independent research career at the University of California San Francisco by building on his previous experience and training. This will be accomplished through a mentored research project supervised by Dr. Israel F. Charo, and additional training in immunology and use of transgenic mouse models. Dr. Gupta is a pediatric neurosurgeon with a clinical and research interest in neuro-oncology. His project, 'Macrophage and microglial activation in glioma-associated inflammation1 addresses an understudied aspect of brain tumor biology: the interactions between inflammatory cells and tumor cells. The hypothesis of this project is that macrophages and microglia are recruited to high-grade gliomas by overexpression of a specific chemokine, monocyte chemoattractant protein-1 (MCP-1), and that this process facilitates tumor growth. The specific aims that will test this hypothesis are: a) determine the origin of tumor-associated macrophages, b) measure the effect of loss of the CCR2 cytokine receptor on glioma growth in mice developing oligodendrogliomas, and c) determine the contribution of tumor and host-derived MCP-1 on glioma growth. The importance of MCP-1 is suggested by its ubiquity in high-grade gliomas, its correlation with infiltrating macrophages, and data supporting a role for this cytokine in angiogenesis and tumor cell migration. The effect of macrophages and microglia on glioma growth will be directly examined using a genetic approach in transgenic mice. Mice expressing the v-erbB oncogene in a heterozygous ink4a/arf background develop high-grade tumors with a predictable incidence. These tumors recapitulate many of the features of human high-grade tumors. For specific aim 1, animals will receive bone marrow transplants with fluorescently labeled cells so that bone- marrow derived cells can be identified precisely. The effect of cytokine activity upon glioma growth will be measured in specific aim 2 by crossing v-erbB expressing mice with mice that lack CCR2, the cellular receptor for MCP-1. Macrophage and microglia will be measured using immunohistochemistry and flow cytometry. The final specific aim will use intracranial implantation of transformed astrocytes to study the effect of either tumor- or host-derived MCP-1 on tumor growth. If the expected results are achieved, we would next evaluate inhibitors of the MCP-1/CCR2 signaling pathway as potential anti-tumor agents. Public Health Relevance: Inflammation accompanying malignant brain tumors results in complications for patients, and may promote the growth of tumors. Identifying the role of inflammation in brain tumors would provide a rationale to develop drugs to target this process. Another possible benefit of such drugs is that normal tissue injury associated with treatments such as radiation may also be reduced.