胃癌是亚洲人高发肿瘤，环境因素与遗传基因均与其发病有关。ALDH2是乙醇-乙醛-乙酸代谢通路的关键酶，通过降解醛类保护DNA免受损伤。ALDH2第12外显子rs671基因多态性有种族差异，欧美人呈ALDH2*1型（野生型），而东亚人ALDH2*2（变异型）携带比例较高，G>A置换导致编码氨基酸改变及酶活性丧失，又被称为“东方人变异”。我们推测：亚裔人高比例的ALDH2*2基因型与胃癌高发可能存在关联，但尚需实验验证。本项目拟从体外细胞模型与Aldh2基因敲除小鼠层面研究ALDH2失活的胃黏膜对MNU、幽门螺杆菌、酒精等因素暴露的DNA损伤与癌变程度；研究向Aldh2*2基因型小鼠补充酶激动剂恢复酶活性对胃黏膜的保护作用；分析ALDH2缺陷型胃癌细胞对不同化学药物的反应性差异。该课题有望对亚洲人胃癌高发现象提供科学合理解释，还将揭示ALDH2酶缺陷胃癌细胞的化学药物应答特征供个体化用药参考。

Gastric cancer dominantly occurs in Asia. Except the diet habit, the genetic variation is also a causal factor. ALDH2 is the key enzyme for the metabolic pathway of alcohol-acetaldehyde-acetic acid, which protect cellular DNA from damage through degradation of toxic aldehydes. There is a single nucleotide polymorphism on exon 12 (rs671) of ALDH2 between different ethnics. Western people carries ALDH2*1(wild type), while as high as 40% of East Asian peoples carry ALDH2*2 (variant type). The single nucleotide replacement of G>A of ALDH2*2 can cause amino acid substitution (Glu504Lys), and then loss enzyme activity. So, the genotype of ALDH2*2 is also called "oriental variation". We speculate that high proportion of ALDH2*2 genotype may associate with the high incidence of gastric cancer in Asian. However, the hypothesis needs to be validated by multiple scientific experiments. This project intends to explore the effects on mucosa damage and carcinogenesis by means of cell models and Aldh2-knockout mice after we expose cells or mice to chemical carcinogen N-methyl-N-nitrosourea (MNU), helicobacter pylori as well as alcohol. We will observe the extent of DNA injury and malignant transformation on stomach mucosa. The protective effect of ALDH2 to gastric mucosa will be verified when we recover the enzyme activity by administration of ALDH2 agonist Alda-1 (N-[1, 3-benzodioxol-5-ylmethyl]-2, 6- dichlorobenzamide) in vivo. Since some study revealed that cancer cells with ALDH2*1 is resistant to doxorubicin drug, we will analyze the reaction of stomach cancer cells with deficient ALDH2 activity to different chemical drugs. The project is expected to provide a scientific explanation of the special phenomenon that East Asian peoples carry high percentage of ALDH2*2 genotype and present high incidence of stomach cancer. The project will also reveal the drug-responsive characteristics of gastric cancer cells with deficient ALDH2 activity and provide the useful reference for personalized medicine.