The Roles of Microglia and Macrophage Populations in the Glioma Microenvironment

描述(申请人提供)：本项目旨在描述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。在其他肿瘤情况下，TAMs已被证明与激活的M2巨噬细胞非常相似，并为肿瘤提供促肿瘤因子。实验室以前的工作表明，肿瘤微环境中存在两种潜在的TAMs群体：脑内驻留的小胶质细胞(MG)和骨髓来源的巨噬细胞(BMDM)。为了了解人群之间的差异，我们使用了一种骨髓移植模型，该模型专门用绿色荧光蛋白标记的BMDM，而的MG保持未标记。这使得使用Affymetrix阵列进行分离和转录鉴定成为可能。初步分析显示，与MG相比，骨髓型糖尿病患者体内可选择激活的M2标志物丰富，提示两个人群之间存在功能差异。我的中心假设是：1)GBM中TAM的BMDM和MG群体是不同的极化；2)这种不同的极化以不同的方式影响GBM的发展和进展。我的长期目标是了解哪些因素导致TAM的M2极化不同，这如何影响肿瘤的进展，以及哪些成分是治疗干预的靶点。第一个具体目标将是通过共培养实验来表征体内M1和M2极化的存在以及这种极化可能带来的作用。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之间观察到的不同极化的机制。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。这项工作的意义超越了胶质瘤微环境，提供了对脑转移、其他肿瘤部位、炎性巨噬细胞生物学和免疫介导的神经退行性疾病的洞察。

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.