ROR1的激酶活性和自磷酸化在慢性淋巴细胞白血病中致病机制的研究

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中文摘要
慢性淋巴细胞白血病(CLL)发病率在我国逐年上升,严重威胁国民健康,但其发病机制尚不明确。受体型酪氨酸激酶ROR1在CLL细胞中异常高表达,并参与致癌信号的激活,但其激酶活性的作用尚不清楚。我们的前期实验及文献提示ROR1的激酶活性可能在其介导的致癌信号中起着关键作用。通过独特的ROR1体外激酶活性分析系统,我们发现了ROR1可以进行自磷酸化,并通过质谱发现了自磷酸化位点Y493。在本项目中,我们将在CLL细胞系中表达激酶活性和自磷酸化缺失的突变型ROR1,通过对比野生型,在体外和体内研究其激酶活性和自磷酸化在CLL细胞增殖、迁移和致癌信号通路中的作用机制;我们还将通过CLL患者的白血病细胞临床样本,分析探讨ROR1自磷酸化和CLL疾病进展的关系。本项目将为ROR1信号通路在CLL中的致癌机制提供新的理解,为以ROR1为靶点的小分子抑制剂的研发打下基础,给CLL的新型治疗方法提供突破口。
英文摘要
The prevalence of chronic lymphocytic leukemia (CLL) in China increases significantly in recent years, which has become a threat to public health, but the mechanism of pathogenesis is not fully understood. Receptor tyrosine kinase ROR1 is aberrantly expressed in CLL. Multiple studies have shown that ROR1 is involved in oncogenic cell signals, but the function of its kinase activity is still unknown. Our preliminary data and literatures suggest that the kinase function of ROR1 could be important in ROR1-mediated oncogenic signals. Previously, we detected autophosphorylation of ROR1 in a unique ROR1 kinase assay system. In addition, we identified the autophosphorylation site Y493 of ROR1 by using HPLC-MS/MS. In the proposed study, we aim to study the kinase function of ROR1 in cell proliferation, migration and signaling in vitro and in vivo by using CLL cell lines expressing kinase/autophosphorylation-deficient ROR1 mutant. Furthermore, we will collect leukemia cells from CLL patients and detect autophosphorylation of ROR1. By analyzing clinical data of these patients, we will study the correlation of ROR1 autophosphorylation and disease progression of CLL. These studies will provide new insights into mechanisms of the oncogenic function of ROR1 and the possible clinical application of small molecule inhibitors targeting ROR1 in CLL.
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DOI:10.1186/s12934-021-01559-6
发表时间:2021-03-10
期刊:Microbial cell factories
影响因子:6.4
作者:Zhang D;Guo Y;Zhao Y;Yu L;Chang Z;Pei H;Huang J;Chen C;Xue H;Xu X;Pan Y;Li N;Zhu C;Zhao ZJ;Yu J;Chen Y
通讯作者:Chen Y
DOI:10.3389/fonc.2022.931462
发表时间:2022
期刊:FRONTIERS IN ONCOLOGY
影响因子:4.7
作者:Zhuang, Xiaomei;Pei, Han Zhong;Li, Tianwen;Huang, Junbin;Guo, Yao;Zhao, Yuming;Yang, Ming;Zhang, Dengyang;Chang, Zhiguang;Zhang, Qi;Yu, Liuting;He, Chunxiao;Zhang, Liqing;Pan, Yihang;Chen, Chun;Chen, Yun
通讯作者:Chen, Yun
DOI:--
发表时间:2023
期刊:Experimental Hematology & Oncology
影响因子:10.9
作者:Yuming Zhao;Chunxiao He;Dengyang Zhang;Yao Guo;Zhiyong Peng;Liuting Yu;Na Li;Chun Chen;Zhizhuang Joe Zhao;Yun Chen
通讯作者:Yun Chen
DOI:10.1530/REP-22-0367.
发表时间:2023
期刊:Reproduction
影响因子:--
作者:Lin Chen;Weijie Zhao;Mengxiong Li;Yazhu Yang;Chengzi Tian;Dengyang Zhang;Zhiguang Chang;Yunzhe Zhang;Zhizhuang Joe Zhao;Yun Chen;Lin Ma
通讯作者:Lin Ma
DOI:10.1038/s41420-022-00884-y
发表时间:2022-02-24
期刊:Cell death discovery
影响因子:7
作者:Guo Y;Pei H;Lu B;Zhang D;Zhao Y;Wu F;Sun H;Huang J;Li P;Yi C;Zhu C;Pan Y;Wu S;Chen C;Xu X;Chen Y
通讯作者:Chen Y
SHP2-Y542磷酸化在幼年型粒单核细胞白血病的临床诊断和靶向治疗中的应用与机制研究
- 批准号:82372312
- 项目类别:面上项目
- 资助金额:49万元
- 批准年份:2023
- 负责人:陈韵
- 依托单位:
国内基金
海外基金
