在调研结肠癌细胞形成CXCR7/CXCR4异二聚体（heterodimer）与组蛋白去甲基化酶JMJD2A表达升高密切相关基础上，建立villin-CXCR4-CXCR7小鼠，发现CXCR4/CXCR7 heterodimer促进炎癌转化。假设CXCR7通过信号偏移促使CXCR4/CXCR7 heterodimer直接与β-arrestin1结合并促进入核，核内β-arrestin1促使JMJD2A催化组蛋白H3K9me3和H3K36me3去甲基化。拟以荧光共振能量转移（FRET）技术分析CXCR4/CXCR7 heterodimer与β-arrestin1直接结合，分析信号转导偏移；以ChIP、PCR及Western blot分析关联基因转录；以甲基化芯片分析参入应答信号偏移所致组蛋白去甲基化位点；设计靶向CXCR4/CXCR7 heterodimer抑制剂，探索结直肠癌治疗新策略。

We previously found that CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A in human colorectal rectal cancer tissues. In order to investigate the mechanism of colorectal tumorigenesis, we generated mice models with high expression of CXCR4/CXCR7 heterodimer. CXCR4/CXCR7 heterodimer was determined a major stimulator of the pathogenesis of colitis and colorectal tumorigenesis. we hypothesize that CXCR7 as an atypical G protein-coupled receptor (GPCR) might lead to CXCR4/CXCR7 heterodimer to bind with β-arrestin through mechanism of signal bias and then induce histone demethylation. We aim to investigate the mechanism of signal bias for CXCR4/CXCR7 heterodimer in the pathogenesis of colitis and colorectal tumorigenesis. Fluorescence resonance energy transfer (FRET) assay will be used to analyze signal bias of CXCR4/CXCR7 heterodimer in inducing nuclear β-arrestin. Ch-IP kits will be used to determine histone demethylase activity. Chromatin immunoprecipitation (Ch-IP) assay with antibodies to demethylase will be performed to determine the transcription of downstream genes. ChIP, PCR and Western blot assays will be used to confirm the levels of the transcriptions and promoters bound to the histones in colorectal cancer tissues. We try to design CXCR4/CXCR7 heterodimer inhibitors for investigating new methods of CRC therapies through inhibition of CXCR7/CXCR4 heterodimer-induced histone demethylation.