MACROPHAGE AND MICROGLIAL ACTIVATION IN GLIOMA-ASSOCIATED INFLAMMATION
Gupta Nalin, Associate Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5K08NS055061-05 from National Institute Of Neurological Disorders And Stroke
Abstract: The goal of this project is to provide , 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. 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
Keywords: 0-11 years old; 21+ years old; adaptive immunity; Address; Adult; adult human (21+); Anaplastic Astrocytic Neoplasm; Anaplastic Astrocytic Tumor; Anaplastic astrocytoma; angiogenesis; Animals; antitumor agent; Astrocytes; Astrocytoma, Grade III; Astrocytus; Astroglia; Attenuated; beta-Chemokines; Binding; Binding (Molecular Function); Blood monocyte; Blood Vessels; Body Tissues; Bone Marrow; Bone Marrow Transplant; Bone Marrow Transplantation; Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; C-C Chemokines; Cachectin; Cachectin-Tumor Necrosis Factor; California; Cancer Genes; cancer metastasis; Cancer of Brain; Cancer-Promoting Gene; career; CCL2; CCL2 gene; CCR2 receptor; Cell/Tissue, Immunohistochemistry; Cells; Central Nervous System Diseases; Central Nervous System Disorders; Central Nervous System Neoplasms; chemoattractant cytokine; chemokine; chemokine receptor; Chemokines, CC; Child; Child Youth; Childhood; children; Children (0-21); Chronic; Clinical; clinical relevance; Clinical Research; Clinical Study; clinically relevant; CNS Diseases; CNS disorder; CNS neoplasm; CNS Tumor; Cytofluorometry, Flow; cytokine; Cytokine Receptors; Cytokines, Chemotactic; Data; Demyelinations; Development; Disease; disease/disorder; Disorder; drug/agent; Drugs; Ectopic Expression; Encephalon; Encephalons; Endothelial Cells; Environment; experience; Extracellular Matrix, Integrins; Family; Flow Cytofluorometries; Flow Cytometry; flow cytophotometry; Flow Microfluorimetry; G-Proteins; GDCF-2; GDCF-2 HC11; Generalized Growth; Genetic; gitter cell; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioma; Goals; Grade III Astrocytic Neoplasm; Grade III Astrocytic Tumor; Grafting, Bone Marrow; Growth; GTP-Binding Proteins; GTP-Regulatory Proteins; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; HC11; Hematogenous; Histologic; Histologically; Homologous Chemotactic Cytokines; Hortega cell; Human; Human, Adult; Human, Child; Human, General; Hypoxia; Hypoxic; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; Immunology; Immunology (Including BRMP); Immunology (NCI Program); immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Implant; implantation; In Vitro; Inbred Strains Mice; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; INFLM; inhibitor; inhibitor/antagonist; Injury; insular sclerosis; Integrins; Intercrines; interest; Investigators; Israel; Knock-out; Knockout; Knockout Mice; Label; Ligands; local drug delivery; loss of function; macrophage; malignant astrocyte; Malignant Astrocytoma; Malignant neoplasm of brain; Malignant Tumor of the Brain; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow monocyte; Marrow Transplantation; MCAF; MCP-1; MCP1; Measures; Mediating; Medication; Mentors; mesoglia; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; MGC9434; Mice; Mice, Knock-out; Mice, Knockout; Microfluorometry, Flow; Microglia; microglial cell; microgliocyte; migration; Molecular Interaction; monocyte; monocyte chemoattractant protein 1 receptor; Monocyte Chemoattractant Protein-1; Monocyte Chemotactic and Activating Factor; Monocyte Chemotactic and Activating Protein; Monocyte Chemotactic Protein-1; Monocyte Secretory Protein JE; mouse model; MS (Multiple Sclerosis); Multiple Sclerosis; Murine; Mus; Natural immunosuppression; Necrosis; Necrotic; Neoplasm Metastasis; Neoplasms of Neuroglia; neoplastic cell; Nervous System, Brain; neuro-oncology; Neuroglial Neoplasm; Neuroglial Tumor; Neurosurgeon; Nomenclature; Normal Tissue; Normal tissue morphology; Null Mouse; oligodendroglioma; Oncogenes; ontogeny; overexpression; Oxygen Deficiency; Pathogenesis; Patients; pediatric; perivascular glial cell; Pharmaceutic Preparations; Pharmaceutical Preparations; Play; Primary Brain Neoplasms; Process; programs; Programs (PT); Programs [Publication Type]; public health relevance; R01 Mechanism; R01 Program; Radiation; ray (radiation); receptor; Receptor Protein; receptor, MCP-1; recruit; Recruitment Activity; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Specimen; Researchers; Resistance; resistant; response; Reticuloendothelial System, Bone Marrow; Role; RPG; San Francisco; Sclerosis, Disseminated; SCYA2; Secondary Neoplasm; Secondary to; Secondary Tumor; Signal Pathway; SIS cytokines; Small Inducible Cytokine A2; small molecule; SMC-CF; social role; Specimen; Stimulus; SUBGP; Subgroup; surgeon, neuro-; SYS-TX; System; System, LOINC Axis 4; Systemic Therapy; Target Populations; Testing; Therapeutic Agents; Tissue Growth; tissue processing; Tissues; TNF-alpha; Training; Transforming Genes; Transgenic Mice; tumor; Tumor Biology; Tumor Cell; Tumor Cell Migration; tumor growth; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Tumor-Derived; tumors in the brain; tumors in the central nervous system; Tumors of Neuroglia; Tumors, Central Nervous System; Universities; v erbB; v-erbB Gene; v-erbB Oncogenes; vascular; Viral Diseases; viral infection; Virus Diseases; virus infection; youngster
Project start date: 2006-04-19
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-00-003
5K08NS055061-05 (2010): $161406
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