我们前期研究发现在肺腺癌中某些癌基因突变（如Kras）能激活生长信号通路，并上调内源性组织金属蛋白酶抑制剂Timp-1蛋白的表达量。Timp-1高表达能通过正反馈机制进一步促进细胞增殖。在动物模型中，抑制肿瘤细胞的Timp-1表达能阻止细胞增殖并延长小鼠存活期。另外肺腺癌病人样品中Timp-1高表达与低存活期相对应。因此我们推断在肺腺癌病人中抑制Timp-1表达也将起到类似的治疗效果。本项目中我们将检测本科收治肺腺癌病人肿瘤样品中的Timp-1表达量，进一步明确其与癌基因突变和存活期的相关性。另外我们将在细胞水平上研究癌基因是如何上调Timp-1表达，以及Timp-1是如何通过结合其细胞表面受体CD63并活化生长信号通路的分子机制。基于这些结果我们将制备Timp-1阻断性单抗，并在细胞和动物水平上验证其阻断细胞增殖和肿瘤生长的效果，为下一步应用到临床治疗提供理论基础。

Our preliminary results indicate that certain oncogenic mutations (such as Kras) can upregulate Timp-1 expression. Timp-1 high expression stimulates cell proliferation through a positive-feedback mechanism. Furthermore, high Timp-1 expression usually links to poor prognosis in human lung adenocarcinoma patients. Thus we think Timp-1 blocking strategy may benefit human lung cancer patients as well. In this study, we will carefully examine Timp-1 expression in the tumor samples derived from our thoracic surgeries and confirm the relation among Timp-1 expression, oncogenic mutations and patient survival. Besides, we will study how these oncogenic mutations activate Timp-1 expression and how Timp-1 binds to its receptor CD63 and stimulates cell proliferation at molecular levels. We will develop blocking antibodies against Timp-1/CD63 interaction based on this information and test the efficacy of these blocking antibodies against cancer cell proliferation and tumor development in animals. Our result will serve as a proof-of-principle for the application of Timp-1 blocking antibodies in cancer therapy.