CSF1 signaling in gliomagenesis

神经胶质瘤发生中的 CSF1 信号传导

基本信息

批准号：
9477789
负责人：
Lara S Collier
金额：
$ 32.57万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9477789
关键词：
Acceleration Address Apoptosis Autocrine Communication Biological Brain CSF1R gene Cell Proliferation Cell Survival Cell physiology Cells Central Nervous System Diseases Clinical Trials Colony-Stimulating Factor Overexpression Conflict (Psychology)Development Genetic Glial Fibrillary Acidic Protein Glioma Gliomagenesis Homeostasis Human Immune Infiltration Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Mesenchymal Microglia Modeling Morbidity - disease rate Mus Neuraxis Paracrine Communication Pathology Patients Peripheral Pharmaceutical Preparations Phenotype Phosphotransferases Reporting Research Resistance Role Signal Transduction Signaling Molecule System Testing Therapeutic Time Tissue Model Transgenic Mice Transgenic Model Transgenic Organisms Tumor Initiators Tumor-infiltrating immune cells Up-Regulation Work autocrine cancer stem cell cell type chemotherapy experimental study genetic approach in vivo inhibitor/antagonist interest loss of function macrophage migration mouse model neoplastic cell overexpression paracrine predictive marker public health relevance response response biomarker small molecule inhibitor targeted treatment tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Current glioma therapies only modestly prolong survival and therefore there is great interest in identifying new targets for glioma treatment. It s hypothesized that targeting cells in the tumor microenvironment such as microglia and macrophages may have therapeutic benefit. We are using genetic approaches to elucidate the actions of Macrophage Colony Stimulating Factor 1 (CSF1) in gliomagenesis. CSF1 is often expressed at high levels in high-grade human gliomas. The CSF1 receptor, CSF1R, is expressed on macrophages including brain resident macrophages that are called microglia. Microglia and/or peripherally derived macrophages are a major component of the microenvironment in high-grade gliomas. In some human gliomas, CSF1R is also expressed on tumor cells, suggesting a possible additional autocrine role for CSF1 signaling in gliomagenesis. One small molecule inhibitor of CSF1R is in clinical trials for glioma. However, the actions of CSF1 signaling on glioma initiation and progression in vivo have not previously been studied in a genetically tractable system. CSF1 signaling through CSF1R can promote multiple cellular responses including proliferation, migration, survival or differentiation. Therefore, in order to understand the therapeutic implications of CSF1R blockade, it is important to elucidate the impacts of both autocrine and paracrine CSF1 signaling during gliomagenesis in vivo. Specifically, the proposed research will determine the roles of CSF1 and CSF1R in glioma initiation and progression in a transgenic mouse glioma model. The impact of CSF1 on phenotypes of glioma-associated macrophages/microglia will be determined. Genetic gain- and loss-of-function experiments in mice will be used to dissect autocrine and paracrine CSF1 actions during gliomagenesis. The contribution of CSF1 autocrine signaling to human glioma cancer stem cell proliferation and survival will also be investigated. The ability of CSF1R blockade to impact the numbers and phenotypes of glioma-associated macrophages/microglia will be determined and the ability of CSF1 or CSF1R levels to influence response to CSF1R-directed therapy tested. The impacts of CSF1R specific and non-specific inhibitors on other tumor-associated immune cells will be determined, as will the ability of CSF1R inhibition to cooperate with a standard chemotherapeutic. In summary, the work proposed here includes detailed in vivo studies to elucidate the biological effects of CSF1 autocrine and paracrine signaling in gliomagenesis; and to determine how to best exploit CSF1 signaling as a target for glioma therapy. As high levels of CSF1 are found in multiple CNS diseases, the results of this study may have therapeutic implications in many CNS pathologies.

描述（由申请人提供）：目前的神经胶质瘤治疗只能适度延长生存期，因此人们对确定神经胶质瘤治疗的新靶点非常感兴趣。据推测，针对肿瘤微环境中的细胞（例如小胶质细胞和巨噬细胞）可能具有治疗益处。我们正在使用遗传学方法来阐明巨噬细胞集落刺激因子 1 (CSF1) 在神经胶质瘤发生中的作用。 CSF1 通常在高级人类神经胶质瘤中高水平表达。 CSF1 受体 CSF1R 在巨噬细胞上表达，包括大脑中常驻的巨噬细胞（称为小胶质细胞）。小胶质细胞和/或外周衍生的巨噬细胞是高级神经胶质瘤微环境的主要组成部分。在一些人类神经胶质瘤中，CSF1R也在肿瘤细胞上表达，这表明CSF1信号在神经胶质瘤发生中可能具有额外的自分泌作用。一种 CSF1R 小分子抑制剂正在进行神经胶质瘤的临床试验。然而，之前尚未在遗传易处理系统中研究过 CSF1 信号传导对体内神经胶质瘤发生和进展的作用。通过 CSF1R 的 CSF1 信号传导可以促进多种细胞反应，包括增殖、迁移、存活或分化。因此，为了了解 CSF1R 阻断的治疗意义，阐明自分泌和旁分泌 CSF1 信号在体内胶质瘤发生过程中的影响非常重要。具体来说，拟议的研究将确定 CSF1 和 CSF1R 在转基因小鼠神经胶质瘤模型中神经胶质瘤发生和进展中的作用。将确定 CSF1 对神经胶质瘤相关巨噬细胞/小胶质细胞表型的影响。小鼠遗传功能获得和丧失实验将用于剖析神经胶质瘤发生过程中自分泌和旁分泌 CSF1 的作用。还将研究 CSF1 自分泌信号对人类神经胶质瘤干细胞增殖和存活的贡献。将确定 CSF1R 阻断影响神经胶质瘤相关巨噬细胞/小胶质细胞的数量和表型的能力，并测试 CSF1 或 CSF1R 水平影响对 CSF1R 定向治疗反应的能力。将确定 CSF1R 特异性和非特异性抑制剂对其他肿瘤相关免疫细胞的影响，以及 CSF1R 抑制与标准化疗药物配合的能力。总之，这里提出的工作包括详细的体内研究，以阐明 CSF1 自分泌和旁分泌信号在神经胶质瘤发生中的生物学效应；并确定如何最好地利用 CSF1 信号作为神经胶质瘤治疗的靶标。由于在多种 CNS 疾病中发现高水平的 CSF1，因此这项研究的结果可能对许多 CNS 病理学具有治疗意义。