胶质瘤相关巨噬细胞(GAMs)在胶质母细胞瘤(GBM)中数量众多，是促进GBM恶性演进的关键因素。然而，GAMs向GBM肿瘤微环境募集迁移的机制及诊治意义尚不清楚。我们前期研究发现：GAMs富集于GBM内独特的酸性微环境中，且酸性微环境增强GAMs迁移能力；酸性感受蛋白GPR65及其下游分子CREM在GAMs中高表达，并与细胞迁移运动相关蛋白ADAM9的表达呈正相关。因此推测：肿瘤酸性微环境通过GPR65/CREM/ADAM9通路促进GAMs的募集迁移。本课题将应用肿瘤标本、小鼠原位种植瘤模型和3D水凝胶迁移实验等体内外二维三维实验体系，研究酸性微环境通过GPR65调控GAMs募集迁移的机制；明确GPR65/CREM对ADAM9的表达调控；验证靶向GPR65抑制GAMs募集迁移及GBM进展的作用。本研究有望阐明GBM酸性微环境招募GAMs的具体机制，为GBM靶向治疗提供新思路。

Glioma-associated macrophages (GAMs) are numerous in glioblastoma (GBM) and play important roles in the malignant progression of GBM. However, the underlying mechanisms and clinical significance of GAMs migration to the GBM tumor microenvironment remain to be elucidated. Our preliminary study found that GAMs infiltration is enriched in the GBM unique acidic microenvironment which enhances the GAMs migration. The pH-sensitive protein GPR65 and its downstream factor CREM are highly expressed in GAMs, and they are closely associated with the expression of ADAM9 which is involved in cell migration. Therefore, we proposed that that the tumor acidic microenvironment regulated the recruitment and migration of GAMs through the GPR65/CREM/ADAM9 pathway. Our study will use the human GBM specimens, orthotopic mouse GBM model and 3D hydrogel migration assays to explore the regulatory mechanism of GAMs recruitment and migration by GPR65 in acidic microenvironment; clarify the regulation of ADAM9 expression by GPR65/CREM and verify the effect of targeting GPR65 on the inhibition of GAMs migration and GBM growth. Our research is expected to elucidate the specific mechanism underlying GAMs recruitment in GBM acidic microenvironment and shed lights on new targeted therapies for GBM treatment.