The Roles of Microglia and Macrophage Populations in the Glioma Microenvironment

描述（由申请人提供）：本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）微环境中的作用。在其他肿瘤背景下，TAM已被证明与交替活化的M2巨噬细胞非常相似，并为肿瘤提供促肿瘤发生因子。实验室先前的工作表明，肿瘤微环境中存在两种潜在的TAM群体：脑驻留小胶质细胞（MG）和骨髓源性巨噬细胞（BMDM）。为了理解群体之间的差异，我们利用骨髓移植模型，用GFP特异性标记TAM BMDM，而TAM MG保持未标记。这允许使用Affyphase阵列进行分离和转录表征。初步分析表明，与TAM MG相比，TAM BMDM中交替激活的M2标志物富集，表明两个群体之间的功能差异。我的主要假设是：1）GBM中TAM的BMDM和MG群体是差异极化的，和2）这种差异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的差异M2极化，这如何影响肿瘤进展，以及哪些成分是治疗干预的目标。第一个具体的目的将是表征M1和M2极化TAM在体内的存在以及这种极化可能赋予使用共培养实验的作用。第二个具体目标将研究M2极化如何在体内调节肿瘤进展，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来探索TAMs中的转录网络，并开发基因表达特征，以帮助该领域了解TAMs在肿瘤进展中的作用。这项工作的影响超出了胶质瘤微环境，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见解。

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.