NON ANTIBIOTIC PROPERTIES OF TETRACYCLINES

本申请寻求补充支持一个新的和独特的戈登研究会议题为“四环素和其他抗生素的非抗生素性质。”1983年，Golub等人。研究牙周病的发病机制，发现某些四环素（TC）药物抑制基质金属蛋白酶（MMPs）的作用，而不依赖于它们的抗菌能力。这一关于MMPs的观察结果已在超过25个实验室得到证实。其机制包括对基因表达、激活和酶活性的影响。许多科学家随后扩展了我们对TCs的非抗生素特性以及此类制剂的潜在应用的认识。目前已知TCs可抑制血管生成，抑制癌细胞侵袭和转移，调节基因表达，改善糖尿病，恢复成骨细胞/破骨细胞功能，抑制iNOS和其他基因的表达。存在TC类似物，其中化合物的抗微生物特性已被删除，但保留了抗mmp能力。这些药物，现在被称为cmt（化学修饰四环素），已被证明具有适用于许多疾病过程的多种宿主调节作用。除了牙周病的标志性应用外，现在有证据表明tc / cmt可能对癌症、关节炎、眼睛和皮肤疾病、代谢性骨病、动脉瘤和动脉粥样硬化有用。新的作用机制正在研究中，这可能阐明TC的药理学，因此对各种健康问题具有重要意义。本次会议是第一次将这一新兴领域的主要研究人员聚集在一起的GRC，并将重点交流有关有前途的TC研究生物学模型，分子作用机制和TC药理学的新信息，特别强调癌症。预计这次会议将通过促进互动合作和建立一个讨论未来研究方向的论坛，对这一迅速兴起的领域产生重大影响。

This application seeks supplemental support for a new and unique Gordon Research Conference entitled "Non-Antibiotic Properties of Tetracyclines and Other Antibiotics." In 1983, Golub et.al., studying the pathogenesis of periodontal disease, discovered that certain tetracycline (TC) drugs inhibited the action of matrix metalloproteinases, (MMPs) independent of their antimicrobial capacity. This observation regarding the MMPs has since been confirmed in over 25 laboratories. The mechanism(s) include effects on gene expression, activation, and enzymatic activity. Many scientists have subsequently extended our knowledge of the non- antibiotic properties of TCs as well as the potential applications of such agents. TCs are now known to inhibit angiogenesis, to suppress cancer cell invasion and metastasis, to regulate gene expression, to ameliorate diabetes, to restore osteoblast/clast function, and to inhibit expression of iNOS and other genes. TC analogues exist from which the anti-microbial properties of the compound have been deleted with retention of the anti-MMP capacity. These agents, known now as CMTs (chemically modified tetracyclines), have since been shown to have a wide variety of host-modulating actions applicable to many disease processes. In additional to their signature application for periodontal disease, there is now evidence that TCs/CMTs may be useful in cancer, arthritis, eye and skin disease, metabolic bone disease, aneurysm, and atherosclerosis. New mechanisms of action of TCs are under investigation, which may elucidate TC pharmacology, and consequently have important implications in a variety of health issues. This Conference represents the first GRC which will bring together leading researchers in this emerging field, and will focus on the exchange of new information regarding promising biological models for TC investigation, molecular mechanisms of action and pharmacology of TC, with particular emphasis on cancer. This Conference is expected to have a significant impact on this rapidly emerging field by fostering interactive collaborations and establishing a forum for discussions regarding the direction of future research.