BACTERIAL PROTEINASES IN PERIODONTAL DISEASE

描述(申请人提供)：牙周病发生和发展的主要微生物是牙周病原体，牙龈卟啉单胞菌。这种细菌利用大量的毒力因子来避免宿主防御，允许其在感染部位生长和繁殖。在这些因素中有蛋白水解酶，它们似乎参与了级联通路的解除调控，血浆蛋白水解酶抑制物的失活，以及趋化过程的破坏，所有这些都有利于入侵的有机体。这些酶中的许多已经在这个实验室中被分离和表征，显然，针对它们开发的抑制剂将显著减少与牙周炎相关的病理症状。然而，在某些类型的牙周疾病中，特别是在其早期阶段，可能涉及其他细菌病原体。因此，该项目的具体目标如下：1)扩展我们开发的直接指向牙周病病理特征(探诊出血、肿胀、组织吸收、骨质丢失)中主要作用的模型；2)启动实验以确定在牙周病早期发现的其他细菌病原体是否也利用蛋白水解酶来逃避宿主防御；3)筛选和纯化可能由其他口腔生物合成的低分子和高分子量的蛋白水解酶抑制物，以可能控制牙周炎的生长和增殖。我们的长期目标是确定牙龈假单胞菌用来避免宿主防御的机制是否为其他病原体所采用的一般过程，并开发针对这些酶的抑制剂，以控制或根除细菌感染。

DESCRIPTION (provided by applicant): A primary organism involved in the development and progression of periodontal disease is the periodontopathogen, Porphyromonas gingivalis. This bacterium utilizes an arsenal of virulence factors to avoid host defense, allowing for its growth and proliferation at infected sites. Among these factors are proteolytic enzymes, which appear to be involved in the deregulation of cascade pathways, the inactivation of plasma proteinase inhibitors, and the disruption of chemotactic processes, all to the benefit of the invading organism. Many of these enzymes have been isolated and characterized in this laboratory, and it seems clear that inhibitors developed against them would significantly reduce the pathological symptoms associated with periodontitis. Nevertheless, in some types of periodontal disease, especially its early phase, other bacterial pathogens are likely to be involved. For these reasons, the Specific Aims of this project are as follows: 1) to expand the model we have developed which directly points to major roles for P. gingivalis proteinases in the pathological hallmarks of periodontal disease (bleeding on probing, swelling, tissue resorption, bone loss), 2), to initiate experiments to determine if other bacterial pathogens which are found at the early stages of periodontal disease also utilize proteolytic enzymes for host defense evasion, and 3) to screen for and purify low and high molecular weight proteinase inhibitors which may be synthesized by other oral organisms for the possible control of P. gingivalis growth and proliferation. Our long-term goals are to determine whether the mechanisms used by P. gingivalis to avoid host defense are a general process that other pathogens have adopted and to develop inhibitors against such enzymes in order to control or eradicate bacterial infections.