Dysregulation of intestinal morphogen gradients leads to ectopic stem-cell properties in intestinal neoplasia and inflammation/restitution

肠道形态发生素梯度失调导致肠道肿瘤和炎症/恢复中的异位干细胞特性

• 批准号: MR/L016508/1
• 负责人: Sujata Biswas
• 金额: $ 32.99万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL016508%2F1
• 关键词: Dysregulation; intestinal; morphogen; gradients; leads

The human gut is made up of units called crypts, in which all cell types within it are derived from the stem cells housed at the crypt base. Control of these stem cells is thought to occur from the action of chemical messages secreted by cells that surround the stem cell. Derangement of these messages can lead to abnormal stem-cell growth leading to colorectal cancer formation which affects 39,000 people a year in the UK and is responsible for more than 16,000 deaths annually. Intestinal inflammation is common, with inflammatory bowel disease affecting up to 2% of the population. Longstanding (chronic) intestinal inflammation and repair is a significant risk factor for cancer development. We hypothesise that inherited or sporadic genetic mutations and chronic intestinal inflammation and repair can dysregulate the delicately balanced chemical messages that control the stem-cell and that this disruption can lead to loss of control of stem-cell division, initiating tumour formation.A team of clinicians and scientists intend to examine these functional mechanisms using biological models to mimic the changes seen in early tumourigenesis and in intestinal damage and repair. We believe that this work will lead to a better understanding of tumour development and growth, help to determine whether measurement of pathway disruption may predict patients' risk of cancer development and highlight potential target areas for anti-cancer treatment.

人类肠道是由称为隐窝的单位组成的，其中所有的细胞类型都来自于隐窝底部的干细胞。对这些干细胞的控制被认为是通过干细胞周围细胞分泌的化学信息的作用而发生的。这些信息的紊乱会导致干细胞的异常生长，从而导致结直肠癌的形成。在英国，结直肠癌每年影响3.9万人，每年导致1.6万多人死亡。肠道炎症是常见的，炎症性肠病影响高达2%的人口。长期（慢性）肠道炎症和修复是癌症发展的重要危险因素。我们假设遗传或零星的基因突变和慢性肠道炎症和修复可以失调控制干细胞的微妙平衡的化学信息，这种破坏可能导致失去对干细胞分裂的控制，引发肿瘤的形成。一组临床医生和科学家打算用生物学模型来模拟在早期肿瘤发生和肠道损伤和修复中所见的变化来检查这些功能机制。我们相信这项工作将有助于更好地了解肿瘤的发展和生长，有助于确定途径破坏的测量是否可以预测患者的癌症发展风险，并突出潜在的抗癌治疗靶点。

项目成果

AODTH-004 Intestinal epithelial-mesenchymal signalling pathways in homeostasis and inflammation

AODTH-004 稳态和炎症中的肠上皮间质信号通路

• DOI: 10.1136/gutjnl-2017-314472.391
• 发表时间: 2017
• 作者: Biswas S

Microenvironmental control of stem cell fate in intestinal homeostasis and disease.

• DOI: 10.1002/path.4563
• 发表时间: 2015-10
• 期刊: The Journal of pathology
• 作者: Biswas S;Davis H;Irshad S;Sandberg T;Worthley D;Leedham S
• 通讯作者: Leedham S

Evolutionary history of human colitis-associated colorectal cancer.

• DOI: 10.1136/gutjnl-2018-316191
• 发表时间: 2019-06
• 期刊: Gut
• 影响因子: 24.5
• 作者: Baker AM;Cross W;Curtius K;Al Bakir I;Choi CR;Davis HL;Temko D;Biswas S;Martinez P;Williams MJ;Lindsay JO;Feakins R;Vega R;Hayes SJ;Tomlinson IPM;McDonald SAC;Moorghen M;Silver A;East JE;Wright NA;Wang LM;Rodriguez-Justo M;Jansen M;Hart AL;Leedham SJ;Graham TA
• 通讯作者: Graham TA

Intestinal epithelial-mesenchymal signaling pathways in homeostasis and inflammation

肠道上皮间质信号通路在稳态和炎症中的作用

• 发表时间: 2017
• 作者: Biswas S

Aberrant expression of grem1 leads to ectopic stem cells capable of multilineage potential

grem1 的异常表达导致异位干细胞具有多谱系潜能

• 发表时间: 2017
• 作者: Biswas S