课题基金基金详情
p63+KRT5+KRT7+起源细胞通过Hedgehog通路形成Barrett食管的分子机制研究
结题报告
批准号:
81870380
项目类别:
面上项目
资助金额:
57.0 万元
负责人:
佘军军
依托单位:
学科分类:
H0305.胃酸相关疾病和消化系统神经内分泌调节异常
结题年份:
2022
批准年份:
2018
项目状态:
已结题
项目参与者:
孙祺、Benjamin A.Alman、石承昕、李亚光、韩水平、秦倩、于田雨、时飞宇
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中文摘要
Barrett食管(BE)是含杯状细胞的食管远端鳞-柱状上皮化生,此前BE起源学说的各种模型均未能检测到杯状细胞,因此探寻BE起源细胞一直是该领域亟待解决的重大问题。本课题组首次发现食管鳞-柱状上皮移行区存在BE起源细胞(p63+KRT5+KRT7+),能分化产生含杯状细胞BE(Nature,2017),但作用机制仍待进一步研究。我们又发现,BE起源细胞的Shh和Gli1表达上调,提示Hedgehog(Hh)信号通路处于活化状态,因此推测:胆汁酸返流激活起源细胞的Hh通路,调控BMP4与SOX9等下游基因,驱动肠型上皮化生并形成BE。为证实该假说,拟从临床病理、体外细胞、动物模型三个层次,采用激光共聚焦、FACS、3D共培养、分子生物学等方法,探究Hh通路旁分泌效应的作用方式,及其驱动起源细胞形成BE的分子机制。这将为阐明BE发病机制、开发有效的靶向治疗提供新思路和实验依据。
英文摘要
Barrett esophagus (BE) is an intestinal-like columnar metaplasia that replaces the normal stratified squamous epithelium in the distal esophagus,but the cell origin and formation mechanism of BE is still not clear. Although currently several hypotheses and experimental models have been proposed to explain the pathogenesis of BE, none of them recapitulates the pathological changes characteristically associated with BE in humans, such as the presence of intestinal goblet cells. In our recent research, we creatively found that p63+KRT5+KRT7+ basal cell group in the esophageal squamous columnar epithelium was able to form the BE containing goblet cells, which meant these cells were the original cells of BE (Nature,2017). However, the underlying mechanism of BE formation is still unclear. Recently we found that Shh and Gli1, components of Hedgehog (Hh) signaling pathway, were upregulated in p63+KRT5+KRT7+ basal cell of BE, which meant that Hh pawhway might be involved in the forming process of BE original cells into BE, with the coordination with other cell groups. Based on our preliminary work and the domestic and foreign research, we assume that with the assistance of paracrine growth factors or cytokines from surrounding cell groups, bile acid reflux might activate the Hh pathway of p63+KRT5+KRT7+ basal cells, which could regulate the expression of downstream genes, such as BMP4 and SOX9, and drive squamous epithelium to develop intestinal metaplasia, thus forming BE. This study is the continuation and deepening of the preliminary research foundation. To test our hypothesis, clinical specimens, cell experiments and animal models were processed to define the specific mechanism of Hh pathway in the forming process of p63+KRT5+KRT7+ cells into BE after reflux activating. In addition, laser confocal microscopy, fluorescence activated cell sorting (FACS), 3D cell culture and cell co-culture assays were used to investigate the paracrine effect of non- p63+KRT5+KRT7+ cells on Hh signaling pathway in p63+KRT5+KRT7+ cells, and the mechanism of Hh pathway to induce p63+KRT5+KRT7+ cells to form HE. This study might provide valuable experimental basis and new ideas for the prevention and treatment of BE.
巴雷特食管(BE)是食管腺癌(EAC)的癌前病变。这是一种病理改变,其中鳞状上皮远端食管被柱状上皮取代。胃食管反流引起的胆汁酸盐的长期暴露是肠上皮化生的主要原因。P53 丢失与 BE 的发生有关,并被视为进展的危险因素。我们的数据显示,暴露于胆盐治疗后P53的蛋白表达水平降低,P53缺乏有利于食管上皮细胞的存活,以适应胆盐的刺激并促进肠上皮化生。此外,暴露于胆汁盐酸通过抑制 JAK/STAT 信号通路和激活 P53 缺陷食管上皮细胞中的 VEGFR/AKT信号通路来降低细胞粘附。在EAC临床样本中,P53蛋白表达与ICAM1和STAT3呈正相关,与VEGFR蛋白表达水平呈负相关。这些发现可能阐明p53在食管上皮肠上皮化生进展中的作用,解释P53缺乏作为BE形成进展风险较高的机制,并为EAC提供潜在的治疗靶点。
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DOI:10.3791/62919
发表时间:2022-02-01
期刊:JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
影响因子:1.2
作者:Hu, Chenhao;Zhang, Zhe;She, Junjun
通讯作者:She, Junjun
DOI:10.3389/fonc.2022.930942
发表时间:2022
期刊:FRONTIERS IN ONCOLOGY
影响因子:4.7
作者:Zhang, Lei;Shi, Feiyu;Hu, Chenhao;Zhang, Zhe;Liu, Junguang;Liu, Ruihan;She, Junjun;Tang, Jianqiang
通讯作者:Tang, Jianqiang
Hypomethylated gene NRP1 is co-expressed with PDGFRB and associated with poor overall survival in gastric cancer patients
低甲基化基因 NRP1 与 PDGFRB 共表达,与胃癌患者总生存率较差相关
DOI:10.1016/j.biopha.2019.01.023
发表时间:2019-03-01
期刊:BIOMEDICINE & PHARMACOTHERAPY
影响因子:7.5
作者:Wang, Guanghui;Shi, Bin;She, Junjun
通讯作者:She, Junjun
Development and validation of a new stage-specific nomogram model for predicting cancer-specific survival in patients in different stages of colon cancer: A SEER population-based study and external validation.
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DOI:10.3389/fonc.2022.1024467
发表时间:2022
期刊:Frontiers in oncology
影响因子:4.7
作者:
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阑尾切除术改变肠道微生物组成导致结直肠癌
DOI:10.1038/s41388-022-02569-3
发表时间:2023-03
期刊:ONCOGENE
影响因子:8
作者:Shi, Feiyu;Liu, Gaixia;Lin, Yufeng;Guo, Cosmos Liutao;Han, Jing;Chu, Eagle S. H.;Shi, Chengxin;Li, Yaguang;Zhang, Haowei;Hu, Chenhao;Liu, Ruihan;He, Shuixiang;Guo, Gang;Chen, Yinnan;Zhang, Xiang;Coker, Olabisi Oluwabukola;Wong, Sunny Hei;Yu, Jun;She, Junjun
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  • 批准号:
    82173394
  • 项目类别:
    面上项目
  • 资助金额:
    80万元
  • 批准年份:
    2021
  • 负责人:
    佘军军
  • 依托单位:
一种新型膀胱癌侧群细胞的分离鉴定及其蛋白质组学研究
  • 批准号:
    81072108
  • 项目类别:
    面上项目
  • 资助金额:
    33.0万元
  • 批准年份:
    2010
  • 负责人:
    佘军军
  • 依托单位:
膀胱癌干细胞分离、鉴定及其生物学特性的研究
  • 批准号:
    30600615
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    21.0万元
  • 批准年份:
    2006
  • 负责人:
    佘军军
  • 依托单位:
国内基金
海外基金