抑制mTORC1信号通路对照射引起肠道干细胞损伤的保护作用;

Gastrointestinal syndrome is a common complication of chemotherapy and radiotherapy in abdomen and pelvis, which limits cancer patients treatment. Intestinal stem cells (ISCs) plays a crucial role in intestinal injury and repair. Our recdent stuides and those from others have shown: (1) mTORC1 pathway in intestine was activated at 24 hours after total body irradiation (IR); (2) over activation of mTORC1 pathway in hematopoietc stem cells and hair follicle stem cells is detrimental to their abilities to self renewal and differentiation, leading to stem cell exhaustion;(3) under head and neck irradiation, Rapamycin inhibited the activation of mTORC1 pathway and accerelated the functional restore of epithelium stem cells and the repair of radiation-induced mucosal ulceration. ISCs is a fast proliferating adult stem cell. Based on these novel findings, we will study: (1)determine the regimens of mTORC1 pathway activation induced by irradiation in ISCs;(2)elucidate whether Rapamycin can inhibit IR-induced mTORC1 pathway activation in ISCs and optimze the dose and treatment time window of Rapamycin post irradiation; (3)investigate the protective roles of Rapamycin on IR-induced ISC injury and determine whether Rapamycin mitigates IR-induced lethality in a mouse model; (4)explore the underline mechanisms by which Rapamycin protects ISCs from IR-induced damage, including expression and distribution of tight junction proteins Occludin and ZO-1, quantitative and distribution of ISCs and the status of Wnt pathway in ISCs, which provide new strategies for prevention and treatment of gastrointestinal syndrome and extents to study proliferation and differentiation mechanisms for intestinal stem cells.

胃肠道综合症是腹部和盆部放疗肿瘤病人的常见并发症，目前无较好的治疗方法。肠道干细胞在肠道损伤修复中发挥重要作用。我们和其它学者研究显示：小鼠照射后小肠内mTORC1信号通路可被激活；mTORC1信号通路过度激活会导致小鼠造血干细胞和毛发干细胞衰竭；应用Rapamycin抑制mTORC1信号通路可促进干细胞功能恢复以修复口腔粘膜溃疡。基于这些发现，我们将通过观察和分析照射后肠道干细胞内mTORC1信号通路激活的时相变化、观察照射后不同时间和剂量Rapamycin对肠道干细胞内mTORC1激活的抑制及Rapamycin对照射后肠道干细胞损伤的保护作用，探索照射条件下抑制mTORC1信号通路保护肠粘膜并促进其功能恢复的机制，包括对肠上皮紧密连接蛋白的表达和分布、肠道干细胞的数量及肠道干细胞内Wnt信号通路变化，为深入开展胃肠道综合症的防治提供理论依据，也为肠道干细胞增殖和分化机制研究打下基础。

胃肠道综合症是腹部和盆部放疗肿瘤病人的常见并发症，目前无较好的治疗方法。肠道干细胞在肠道损伤修复中发挥重要作用。有研究显示mTORC1信号通路过度激活会导致小鼠造血干细胞和毛发干细胞衰竭；应用Rapamycin抑制mTORC1信号通路可促进干细胞功能恢复以修复口腔粘膜溃疡。基于以上，我们研究了全身照射后小鼠小肠，我们研究结果表明小鼠X射线全身照射后可造成小肠黏膜损伤、肠黏膜紧密连接蛋白表达下降及肠黏膜屏障功能受损，促进细胞凋亡，导致肠道干细胞损伤；照射后6h mTORC1信号通路即明显被激活，且高剂量X射线照射后其激活随时间增强；采用 Rapamycin抑制肠道mTORC1激活后可减少肠上皮细胞的凋亡，有利于肠道干细胞自我更新和分化能力的恢复及肠粘膜结构和功能的恢复。8GyX射线照射后小鼠于照射后17天全部死亡，而雷帕霉素治疗小鼠照射后30天有25%存活，抑制mTORC1信号通路激活可有效降低由照射导致的小鼠死亡； mTORC1抑制剂雷帕霉素同时也可减轻放射对小鼠肝脏和肾脏的损伤作用，其保护机制可能是通过增加自噬，减少细胞凋亡，并促进细胞增殖。该研究为深入开展照射损伤的防治提供理论依据。