The Roles of Microglia and Macrophage Populations in the Glioma Microenvironment

小胶质细胞和巨噬细胞群在胶质瘤微环境中的作用

• 批准号: 8720720
• 负责人: Robert Lyle Bowman
• 金额: $ 4.27万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2016-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8720720
• 关键词: Accounting; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; B-Lymphocytes; Biological Process; Biology; Bone Marrow; Bone Marrow Transplantation; Brain; Brain Neoplasms; Cell Proliferation; Cells; Characteristics; Coculture Techniques; Computer Analysis; Computing Methodologies; Data; Development; Embryo; Flow Cytometry; Gene Expression Profile; Gene Expression Profiling; Glioblastoma; Glioma; Goals; Hematopoietic System; Immune; Immune system; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Inflammatory; Interferons; Interleukin-13; Interleukin-4; Label; Lead; Link; Macrophage Colony-Stimulating Factor Receptor; Malignant neoplasm of brain; Mediating; Metastatic malignant neoplasm to brain; Microglia; Modeling; Neurodegenerative Disorders; Organ; Paracrine Communication; Patients; Play; Population; Process; Radio; Research; Resistance; Role; STAT6 gene; Signal Transduction; Site; System; Therapeutic Intervention; Work; Wound Healing; Yolk Sac; aggressive therapy; cytokine; in vivo; insight; interest; macrophage; migration; mouse model; neoplastic cell; outcome forecast; reconstitution; research study; stem; transcription factor; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): This project aims to characterize and understand the contribution of tumor associated macrophages (TAMs) in the glioblastoma (GBM) microenvironment. In other tumor contexts, TAMs have been shown to closely resemble alternatively activated M2 macrophages and provide pro-tumorigenic factors to the tumor. Previous work in the lab demonstrates that two potential populations of TAMs are present in the tumor microenvironment: the brain resident microglia (MG) and bone marrow derived macrophages (BMDM). To understand the differences between the populations we utilized a bone marrow transplant model specifically labeling the TAM BMDMs with GFP, while the TAM MG remained unlabeled. This allowed for isolation and transcriptional characterization using Affymetrix arrays. Preliminary analysis demonstrates an enrichment of alternatively activated M2 markers in the TAM BMDM compared to TAM MG suggesting a functional difference between the two populations. My central hypotheses are: 1) the BMDM and MG populations of TAMs in GBM are differentially polarized, and 2) that this differential polarization impacts the development and progression of GBM in different manners. My long term goals are to understand which factors drive the differential M2 polarization of the TAMs, how this affects tumor progression, and which components are targetable for therapeutic intervention. The first specific aim will be to characterize the presence of M1 and M2 polarized TAM in vivo as well as the role that this polarization may confer using co-culture experiments. The second specific aim will investigate how M2 polarization may modulate tumor progression in vivo, with the goal of identifying the mechanisms that drive the differential polarization observed between the BMDMs and MG. The third specific aim will utilize computational methods to explore transcriptional networks in TAMs and develop gene expression signatures to aid the field in understanding the role of TAMs in tumor progression. The implications of this work extend beyond the glioma microenvironment offering insight into brain metastasis, other tumor sites, inflammatory macrophage biology and immune mediated neurodegenerative disorders.

描述（由申请人提供）：该项目旨在表征和了解肿瘤相关巨噬细胞（TAM）在胶质母细胞瘤（GBM）微环境中的贡献。在其他肿瘤环境中，TAM 已被证明与替代激活的 M2 巨噬细胞非常相似，并为肿瘤提供促肿瘤因子。实验室之前的工作表明，肿瘤微环境中存在两种潜在的 TAM 群体：大脑驻留小胶质细胞 (MG) 和骨髓源性巨噬细胞 (BMDM)。为了了解人群之间的差异，我们使用了骨髓移植模型，专门用 GFP 标记 TAM BMDM，而 TAM MG 仍未标记。这允许使用 Affymetrix 阵列进行分离和转录表征。初步分析表明，与 TAM MG 相比，TAM BMDM 中选择性激活的 M2 标记物有所富集，表明两个群体之间存在功能差异。我的中心假设是：1）GBM 中 TAM 的 BMDM 和 MG 群体是不同极化的，2）这种不同极化以不同方式影响 GBM 的发展和进展。我的长期目标是了解哪些因素驱动 TAM 的 M2 极化差异、这如何影响肿瘤进展，以及哪些成分可作为治疗干预的目标。第一个具体目标是表征体内 M1 和 M2 极化 TAM 的存在，以及使用共培养实验这种极化可能赋予的作用。第二个具体目标是研究 M2 极化如何调节体内肿瘤进展，目的是确定驱动 BMDM 和 MG 之间观察到的差异极化的机制。第三个具体目标将利用计算方法探索 TAM 中的转录网络并开发基因表达特征，以帮助该领域了解 TAM 在肿瘤进展中的作用。这项工作的意义超出了神经胶质瘤微环境的范围，提供了对脑转移、其他肿瘤部位、炎症巨噬细胞生物学和免疫介导的神经退行性疾病的深入了解。