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：
7582246
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/7582246
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 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 Primary Brain Neoplasms Process 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 Tissues Training Transgenic Mice 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 overexpression programs public health relevance receptor response small molecule tissue processing tumor tumor growth v-erbB Oncogenes

项目摘要

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.

该项目的目标是为申请人 Nalin Gupta 提供必要的专业知识来开发在他之前的基础上，他在加州大学旧金山分校的独立研究生涯经验和培训。这将通过由博士监督的指导研究项目来完成。 Israel F. Charo，以及免疫学和转基因小鼠模型使用方面的额外培训。古普塔博士是小儿神经外科医生，对神经肿瘤学有临床和研究兴趣。他的项目“巨噬细胞和神经胶质瘤相关炎症中的小胶质细胞激活1解决了脑肿瘤的一个尚未被研究的方面生物学：炎症细胞和肿瘤细胞之间的相互作用。该项目的假设是通过特定趋化因子的过度表达，巨噬细胞和小胶质细胞被招募到高级神经胶质瘤中，单核细胞趋化蛋白-1 (MCP-1)，该过程促进肿瘤生长。具体的检验这一假设的目标是：a）确定肿瘤相关巨噬细胞的起源，b）测量 CCR2细胞因子受体缺失对少突胶质细胞瘤小鼠神经胶质瘤生长的影响， c)确定肿瘤和宿主来源的MCP-1对神经胶质瘤生长的贡献。的重要性 MCP-1 在高级神经胶质瘤中普遍存在，与浸润巨噬细胞相关，并且数据支持该细胞因子在血管生成和肿瘤细胞迁移中的作用。巨噬细胞的作用将使用转基因小鼠的遗传方法直接检查小胶质细胞对神经胶质瘤生长的影响。小鼠在杂合 ink4a/arf 背景中表达 v-erbB 癌基因可形成具有可预测的发生率。这些肿瘤概括了人类高级肿瘤的许多特征。为了具体目标1，动物将接受带有荧光标记细胞的骨髓移植，以便骨- 可以精确识别骨髓来源的细胞。细胞因子活性对神经胶质瘤生长的影响通过将表达 v-erbB 的小鼠与缺乏 CCR2 的小鼠杂交来测量特定目标 2 MCP-1 受体。将使用免疫组织化学和流式细胞仪测量巨噬细胞和小胶质细胞细胞计数术。最终的具体目标是通过颅内植入转化的星形胶质细胞来研究肿瘤或宿主来源的 MCP-1 对肿瘤生长的影响。如果达到预期效果，我们接下来将评估 MCP-1/CCR2 信号通路抑制剂作为潜在的抗肿瘤药物。公共卫生相关性：恶性脑肿瘤伴随的炎症会导致并发症患者，并可能促进肿瘤的生长。确定炎症在脑肿瘤中的作用将为开发针对这一过程的药物提供依据。此类药物的另一个可能的好处是与放射等治疗相关的正常组织损伤也可能减少。