Macrophage and Microglial Activation in Glioma-Associated Inflammation

胶质瘤相关炎症中的巨噬细胞和小胶质细胞激活

基本信息

批准号：
7225185
负责人：
NALIN GUPTA
金额：
$ 16.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-19 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225185
关键词：
Address Adult Anaplastic astrocytoma Animals Astrocytes Attenuated Binding Blood Vessels Bone Marrow Bone Marrow Transplantation Brain Brain Neoplasms CCL2 gene California Cells Central Nervous System Diseases Central Nervous System Neoplasms Child Childhood Chronic Classification Clinical Clinical Research Cytokine Receptors Data Demyelinations Development Disease Ectopic Expression Endothelial Cells Environment Family Flow Cytometry GTP-Binding Proteins Genetic Glioma Goals Growth Hematogenous Histologic Human Hypoxia Immunity Immunohistochemistry Immunology Immunosuppression Implant In Vitro Inbred Strains Mice Incidence Infiltration Inflammation Inflammatory Inflammatory Response Injury Integrins Israel Knock-out Knockout Mice Label Ligands Localized Malignant neoplasm of brain Measures Mediating Mentors Microglia Monocyte Chemoattractant Protein-1 Multiple Sclerosis Mus Necrosis Neoplasm Metastasis Neurosurgeon Nomenclature Normal tissue morphology Oncogenes Pathogenesis Patients Pharmaceutical Preparations Play Process Public Health Radiation Recruitment Activity Research Research Personnel Research Project Grants Resistance Role San Francisco Secondary to Signal Pathway Specimen Stimulus Subgroup System Systemic Therapy Target Populations Testing Therapeutic Agents Therapeutic immunosuppression Tissues Training Transgenic Mice Transgenic Organisms Tumor Biology Tumor Necrosis Factor-alpha Tumor-Derived Universities Virus Diseases angiogenesis antitumor agent beta-Chemokines career chemokine chemokine receptor clinically relevant cytokine experience implantation inhibitor/antagonist interest local drug delivery loss of function macrophage migration monocyte monocyte chemoattractant protein 1 receptor mouse model neoplastic cell neuro-oncology oligodendroglioma programs receptor response small molecule tissue processing tumor tumor growth v-erbB Oncogenes

Address Adult Anaplastic astrocytoma Animals Astrocytes Attenuated Binding Blood Vessels Bone Marrow Bone Marrow Transplantation Brain Brain Neoplasms CCL2 gene California Cells Central Nervous System Diseases Central Nervous System Neoplasms Child Childhood Chronic Classification Clinical Clinical Research Cytokine Receptors Data Demyelinations Development Disease Ectopic Expression Endothelial Cells Environment Family Flow Cytometry GTP-Binding Proteins Genetic Glioma Goals Growth Hematogenous Histologic Human Hypoxia Immunity Immunohistochemistry Immunology Immunosuppression Implant In Vitro Inbred Strains Mice Incidence Infiltration Inflammation Inflammatory Inflammatory Response Injury Integrins Israel Knock-out Knockout Mice Label Ligands Localized Malignant neoplasm of brain Measures Mediating Mentors Microglia Monocyte Chemoattractant Protein-1 Multiple Sclerosis Mus Necrosis Neoplasm Metastasis Neurosurgeon Nomenclature Normal tissue morphology Oncogenes Pathogenesis Patients Pharmaceutical Preparations Play Process Public Health Radiation Recruitment Activity Research Research Personnel Research Project Grants Resistance Role San Francisco Secondary to Signal Pathway Specimen Stimulus Subgroup System Systemic Therapy Target Populations Testing Therapeutic Agents Therapeutic immunosuppression Tissues Training Transgenic Mice Transgenic Organisms Tumor Biology Tumor Necrosis Factor-alpha Tumor-Derived Universities Virus Diseases angiogenesis antitumor agent beta-Chemokines career chemokine chemokine receptor clinically relevant cytokine experience implantation inhibitor/antagonist interest local drug delivery loss of function macrophage migration monocyte monocyte chemoattractant protein 1 receptor mouse model neoplastic cell neuro-oncology oligodendroglioma programs receptor response small molecule tissue processing tumor tumor growth v-erbB Oncogenes

展开

项目摘要

DESCRIPTION (provided by applicant): 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 inflammation' 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 over-expression 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: 1) determine the origin of tumor-associated macrophages, 2) measure the effect of loss of the CCR2 cytokine receptor on glioma growth in mice developing oligodendrogliomas, and 3) 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 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 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.

描述（由申请人提供）：该项目的目的是为申请人Nalin Gupta提供必要的专业知识，以在加利福尼亚大学旧金山分校建立他的先前经验和培训，从而在加利福尼亚大学旧金山分校开发独立的研究生涯。这将通过以色列F. Charo博士监督的指导研究项目以及免疫学和使用转基因小鼠模型的其他培训来实现。 Gupta博士是一种儿科神经外科医生，对神经肿瘤学具有临床和研究兴趣。他的项目“与神经胶质瘤相关的炎症中的巨噬细胞和小胶质细胞激活”介绍了脑肿瘤生物学的研究研究：炎症细胞与肿瘤细胞之间的相互作用。该项目的假设是，巨噬细胞和小胶质细胞通过过度表达特定的趋化因子，单核细胞趋化剂蛋白-1（MCP-1）募集到高级神经胶质瘤中，并且这一过程有助于肿瘤的生长。将检验该假设的具体目的是：1）确定与肿瘤相关的巨噬细胞的起源，2）测量CCR2细胞因子受体丧失的影响，在发生寡头胶质细胞瘤的小鼠中，以及3）确定肿瘤和宿主MCP-1对GlioMoma的贡献。 MCP-1的重要性是由于其在高级神经胶质瘤中的无处不在，与浸润巨噬细胞的相关性以及支持该细胞因子在血管生成和肿瘤细胞迁移中的作用的数据。巨噬细胞和小胶质细胞对神经胶质瘤生长的影响将使用转基因小鼠中的遗传方法直接检查。在杂合子Ink4a/ARF背景中表达V-ERBB癌基因的小鼠会形成可预测发生率的高级肿瘤。这些肿瘤概括了人类高级肿瘤的许多特征。对于特定目标1，动物将接受带有荧光标记细胞的骨髓移植物，以便可以精确地识别出骨髓衍生的细胞。细胞因子活性对神经胶质瘤生长的影响将在AIM 2中通过与缺乏CCR2的小鼠（MCP-1的细胞受体）的小鼠跨越V-ERBB进行测量。巨噬细胞和小胶质细胞将使用免疫组织化学和流式细胞仪测量。最终目标将使用转化的星形胶质细胞的颅内植入来研究肿瘤或宿主衍生的MCP-1对肿瘤生长的影响。如果达到预期的结果，我们将接下来评估MCP-1/CCR2信号通路的抑制剂作为潜在的抗肿瘤剂。公共卫生相关性：伴随恶性脑肿瘤的炎症会导致患者并发症，并可能促进肿瘤的生长。鉴定炎症在脑肿瘤中的作用将提供一种基本原理来开发针对该过程的药物。这种药物的另一个可能的好处是，与辐射等治疗相关的正常组织损伤也可能会降低。