CSF1 signaling in gliomagenesis

描述（由申请人提供）：目前的胶质瘤治疗只能适度延长生存期，因此寻找胶质瘤治疗的新靶点非常有兴趣。假设靶向肿瘤微环境中的细胞如小胶质细胞和巨噬细胞可能具有治疗效果。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）在胶质瘤形成中的作用。CSF1在人类高级别胶质瘤中经常高水平表达。CSF1受体CSF1R在巨噬细胞上表达，包括被称为小胶质细胞的脑内巨噬细胞。小胶质细胞和/或外周来源的巨噬细胞是高级别胶质瘤微环境的主要组成部分。在一些人类胶质瘤中，CSF1R也在肿瘤细胞上表达，这表明CSF1信号在胶质瘤形成中可能具有额外的自分泌作用。一种CSF1R的小分子抑制剂正处于胶质瘤的临床试验中。然而，CSF1信号在体内胶质瘤发生和发展中的作用尚未在遗传可调控的系统中进行过研究。CSF1信号通过CSF1R可促进多种细胞反应，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，阐明体内胶质瘤形成过程中自分泌和旁分泌CSF1信号的影响是很重要的。具体来说，本研究将在转基因小鼠胶质瘤模型中确定CSF1和CSF1R在胶质瘤发生和发展中的作用。CSF1对胶质瘤相关巨噬细胞/小胶质细胞表型的影响将被确定。小鼠遗传功能的获得和丧失实验将用于解剖神经胶质瘤形成过程中自分泌和旁分泌CSF1的作用。CSF1自分泌信号在人类胶质瘤干细胞增殖和存活中的作用也将被研究。将确定CSF1R阻断对胶质瘤相关巨噬细胞/小胶质细胞数量和表型的影响能力，并测试CSF1或CSF1R水平对CSF1R导向治疗反应的影响能力。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胶质瘤形成中的生物学作用；并确定如何最好地利用CSF1信号作为胶质瘤治疗的靶点。由于在多种中枢神经系统疾病中发现了高水平的CSF1，因此本研究的结果可能对许多中枢神经系统病变具有治疗意义。

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.