大黄潜在致癌风险机制及规避策略的研究

大黄是中医临床及减肥保健品中使用频率极高的中药，但是美国国立卫生院及我国国家药监部门均提出大黄具有致癌隐患，这严重制约了大黄在临床中的运用。课题组通过海量文献调研，Arrowsmith相关性分析、计算机虚拟技术及初步实验研究发现大黄中的多种活性成分本身没有致癌性，而是可能由于长期使用大黄导致肠道菌群紊乱所致，并加速K-Ras突变和APC缺失结肠癌高危人群的发展。本项目拟利用K-Ras突变、APC缺失小鼠模型及无菌鼠，结合利用高通量测序分析，CRISPR/Cas9基因工程等技术方法，研究长期使用大黄是否导致肠道菌群稳态失衡而诱发结肠癌，或者加重或加速K-Ras突变和APC缺失小鼠结肠癌的发生发展，明确是否存在致癌隐患并阐明其致癌机制，制定适当的规避策略以指导临床科学合理用药。

Rhubarb is one of the most frequently used Chinese herbs in the clinical practice of Traditional Chinese Medicine. However, reports from both National Institutes of Health (NIH) and SFDA have indicated that long-term use of rhubarb has a potential to cause cancer, which restricts its application in clinic context severely. Based on extensive literature research, Arrowsmith correlation analysis and computer virtual technology as well as preliminary experimental data, we found that the components isolated from rhubarb may not have oncogenic potential directly, instead, long-term use of rhubarb may result in gut microbiota dysbiosis, which may accelerate the disease progress in colon cancer patients with K-Ras mutation and APC deficiency. The current project will use K-Ras mutant and APC deficient mice as well as germ-free mice and employ high throughput sequencing analysis and CRISPR/Cas9 genetic technology, to investigate whether long-term use of rhubarb could cause gut microbiota dysbiosis leading to colon cancer or aggravating the progression of colon cancer with K-Ras mutation and APC deficiency. These studies will clarify the carcinogenic potential of rhubarb and the underlying mechanisms, providing strategy for avoidance of carcinogenic potential of rhubarb and rationale for its clinical application.