INDIVIDUAL PREDOCTORAL DENTAL SCIENTIST FELLOWSHIP

总的研究目标是研究四环素类药物在保护细胞外基质和防止肿瘤转移方面的治疗潜力和作用机制。我特别感兴趣的是TCS新发现的抑制基质金属蛋白酶活性和防止血管生成的能力。这项研究的长期目标是证明TCS，包括缺乏抗菌特性的化学修饰的四环素(CMTs)，可以防止病理性ECM分解。我们特别建议研究一种特殊配方的非抗菌剂TC(CMT-3)在肿瘤细胞培养系统中抑制结缔组织破坏的能力。西蒙博士的实验室建立了一个完整的间质ECM，它将被用来表征肿瘤细胞介导的ECM降解。我们的初步结果表明，肿瘤蛋白酶(基质金属蛋白酶和一种特定的肿瘤丝氨酸蛋白酶，肿瘤相关胰蛋白酶)都有助于人结肠癌细胞系Colo 205的高ECM降解活性。然后，我们打算使用COLO 205作为一个模型系统来研究CMT-3通过抑制肿瘤酶来保护ECM免受破坏的能力和机制。最终目标是将这种癌细胞模型系统上的CMTs的作用与口腔癌联系起来，并选择一种或多种CMTs用于初步的人类临床试验。

The general research goal is to study the therapeutic potential, and mechanisms of action, of tetracyclines(TCs) in protecting extracellular matrix(ECM) and preventing cancer metastasis. My particular interest is in TCs newly discovered ability to suppress the matrix metalloproteinases activity and to prevent angiogenesis. The long-term goal of this research is to demonstrate that TCs, including chemically modified tetracyclines (CMTs) which are devoid antimicrobial properties, can prevent pathologic ECM breakdown. We specifically propose to study the ability of a special formulated non-antimicrobial TC(CMT-3) to inhibit connective tissue breakdown in a tumor cell culture system. A complete interstitial ECM, which is well established in Dr.Simon's lab, will be employed to characterize the tumor cell-mediated ECM degradation. Our preliminary results have demonstrated that tumor proteinases (matrix metalloproteinases and one specific tumor serine proteinase, tumor-associated trypsin) both contributed to the high ECM degradative activities of a human colon carcinoma cell line, COLO 205. We then intend to use COLO 205 as a model system to study the ability and the mechanisms of CMT-3 in protecting ECM from breakdown through its inhibitory effect on tumor enzymes. The ultimate goal is to connect the effect of CMTs on this cancer cell model system to oral cancer and select one or more CMTs for use in preliminary human clinical trial.