Lgr5+结直肠上皮干细胞对电离辐射的反应及机理研究

项目名称： Lgr5+结直肠上皮干细胞对电离辐射的反应及机理研究

项目编号： No.31470826

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物物理、生化与生物分子学、生物力学与组织工程

项目作者： 华国强

作者单位： 复旦大学

项目金额： 85万元

中文摘要： 辐射对肿瘤周围正常肠道组织的损伤是临床腹腔肿瘤放疗的最大限制因素。研究表明电离辐射能对肠道上皮干细胞造成直接损伤导致干细胞死亡，并最终引起正常肠道组织坏死。结直肠上皮干细胞位于隐窝底部能不断自我更新，并产生大量的子代细胞以保证粘膜上皮细胞的快速更新。最新的研究发现小鼠结直肠上皮干细胞特异性表达Lgr5 分子，但是对这群干细胞的辐射敏感性知之甚少。本课题将利用Lgr5 转基因小鼠及体外干细胞3D培养体系，研究Lgr5+结直肠上皮干细胞对电离辐射的反应，包括其消亡指数与辐射引起肠粘膜损伤的相关性，DNA损伤在干细胞中的修复以及干细胞在辐射后肠道粘膜再生中的作用。本课题将阐明正常结直肠上皮干细胞的辐射特性，从而为指导制定更有效的结直肠癌放疗方案和进一步开发干细胞辐射保护剂提供理论基础。

中文关键词： 电离辐射；放射治疗；结直肠癌；肠道干细胞；辐射耐受

英文摘要： Radiation-induced normal intestinal tissue injury is the primary limiting factors in abdominal radiotherapy of human tumors. According to the prevailing hypothesis, it is caused by direct damage to intestinal stem cells , resulting in their death.The epithelial lining of the murine coloretum turns over rapidly, a process driven by self-renewing stem cells at the crypt base. Recent studies identify Lgr5+ （leucine-rich-repeat-containing G-protein-coupled receptor 5） epithelial cells located at crypt base as colorectal epithelial stem cells (CESCs). Little is known regarding the sensitivity of this population of stem cells to ionizing radiation.Using lgr5 transgenic mouse model and 3D intestinal stem cell culture system, our goal is to determine how Lgr5+ CESCs respond to ionizing radiation exposures inculding the mechanisms of stem cell death,DNA damage repair, the contribution of CESC to organ loss and tissue regeneration. This project will help us better understand of the properties of lgr5+ CESCs, which are crucial to develop efficient radiotherapeutic strategies to cure colorectal cancer, as well as identification of radioprotetors specicically tailored to protect intestinal stem cell post irradiation.

英文关键词： Ionizing radiation;Radiaiton therapy;Colorectal cancer;Intestinal stem cells;Radioresistance