NON ANTIBIOTIC PROPERTIES OF TETRACYCLINES

本申请寻求对一个新的、独特的戈登研究会议的补充支持，该会议的标题是“四环素和其他抗生素的非抗生素特性”。1983年，Golub等人在研究牙周病的发病机制时发现，某些四环素(TC)药物抑制基质金属蛋白酶(MMPs)的作用，而不是依赖于它们的抗菌能力。自那以后，关于MMPs的这一观察结果已在25个以上的实验室得到证实。其作用机制(S)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天花粉蛋白的非抗生素特性以及这类药物的潜在应用的了解。目前已知TCs具有抑制血管生成、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等基因表达等作用。存在TC类似物，其中化合物的抗微生物特性已被删除，同时保留了抗基质金属蛋白酶的能力。这些药物现在被称为CMTs(化学修饰的四环素类药物)，自那以来已被证明具有广泛的宿主调节作用，适用于许多疾病过程。除了它们用于牙周疾病的标志性应用外，现在有证据表明，TCS/CMTs可能对癌症、关节炎、眼部和皮肤病、代谢性骨病、动脉瘤和动脉粥样硬化有用。TCS的新作用机制正在研究中，这可能会阐明TC的药理作用，因此在各种健康问题上具有重要意义。这次会议是第一次将这一新兴领域的领先研究人员聚集在一起的GRC，并将重点交流关于TC研究的有前景的生物学模型、分子作用机制和TC的药理学的新信息，特别是癌症。预计本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，对这一迅速崛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.