NON ANTIBIOTIC PROPERTIES OF TETRACYCLINES

此申请寻求补充支持，一个新的和独特的戈登研究会议题为“非抗生素性质的四环素和其他抗生素。“1983年，Golub等人，在研究牙周病的发病机理时，发现某些四环素（TC）药物抑制基质金属蛋白酶（MMPs）的作用，而不依赖于它们的抗微生物能力。关于MMP的这一观察结果已在超过25个实验室得到证实。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TC的非抗生素性质以及此类试剂的潜在应用的知识。目前已知TC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/破骨细胞功能以及抑制iNOS和其它基因的表达。存在TC类似物，其中化合物的抗微生物性质已被删除，保留了抗MMP能力。这些药物，现在被称为CMT（化学修饰四环素），已被证明具有广泛的宿主调节作用，适用于许多疾病过程。除了它们在牙周病中的标志性应用之外，现在有证据表明TC/CMT可能在癌症、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中有用。TC的新作用机制正在研究中，这可能阐明TC药理学，因此在各种健康问题中具有重要意义。本次会议代表了第一次GRC，它将汇集这一新兴领域的领先研究人员，并将重点交流有关TC研究的有前途的生物模型，TC的分子作用机制和药理学的新信息，特别强调癌症。本次会议预计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.