S GORDONII AS A VECTOR FOR P GINGIVALIS FIMBRILLIN

描述（改编自研究者摘要）：广泛， 该项目的长期目标是开发一个系统， 产生阻断粘膜感染的生物活性因子。 本申请人提出了开发基因工程菌株， 这种细菌，戈登链球菌， 能够阻断牙龈卟啉单胞菌菌毛蛋白的多肽 粘附和诱导保护性免疫应答。 具体目标 主要有：（1）进一步表征最近开发的表达系统 在我们的实验室中，牙龈卟啉单胞菌菌毛蛋白在S. gordonii;（2）优化S. gordonii为 牙龈卟啉单胞菌菌毛蛋白的产生;和（3）测试这些基因 S.牙周病大鼠模型的研究 用于减少牙龈卟啉单胞菌的定殖和用于防止 破坏性牙周炎 S.选择戈登II是因为它是一个 非致病性口腔微生物，普遍存在于人类口腔 腔，菌株已被基因工程改造，以表达外源 抗原 牙龈卟啉单胞菌是一种重要的病原体， 粘膜感染、牙周病及其菌毛蛋白亚单位的模型 因为它已经被克隆和测序。 此外，P. 牙龈菌毛蛋白结构域参与粘附和免疫 答案已经确定。 重组变异链球菌戈登氏菌株已经被 产生表达菌毛蛋白的生物活性结构域并且具有 表明它们能够在体内产生菌毛蛋白特异性免疫应答， 口服定植后以及胃肠外免疫后的大鼠。 选择牙龈卟啉单胞菌感染的大鼠作为粘膜炎模型， 研究疾病过程的早期步骤，即 坚持和殖民化，因为它是很好的特点，并提供了一个 用于评估遗传工程改造的药物组合物的体内功效的有用模型 干扰毒力的微生物产生因子。 因此，建议进行研究以产生S. 戈登氏菌能够分泌或表面表达重要的菌毛蛋白 肽，并且能够在大鼠模型中调节牙龈卟啉单胞菌感染 牙周病的症状 这些基因工程菌株的S。戈登链球菌 表达菌毛蛋白肽的疫苗可用作抗P. 牙龈感染，并作为一个模型来研究这种新的方法， 其他粘膜感染的疫苗。 该模型还可用于 评价连续表达的生物活性物质的效用 分子的生物体，直接阻止殖民和其他 粘膜感染发病机制的关键早期阶段。

DESCRIPTION (Adapted from the investigator's Abstract): The broad, long-term goal of this project is to develop a system for continuous production of biologically active factors which block mucosal infections. The applicant proposes the development of genetically engineered strains of the commensal organism, Streptococcus gordonii, which expresses Porphyromonas gingivalis fimbrillin polypeptides capable of blocking adherence, and of inducing a protective immune response. The specific aims are: (1) to further characterize the expression system recently developed in our laboratory for P. gingivalis fimbrillin on the surface of S. gordonii; (2) to optimize a secretion system in S. gordonii for the production of P. gingivalis fimbrillin; and (3) to test these genetically engineered strains of S. gordonii in the rat model of periodontal disease for reduction of colonization with P. gingivalis and for protection against destructive periodontitis. S. gordonii was selected since it is a non-pathogenic commensal organism, universally found in the human oral cavity, and strains have been genetically engineered to express foreign antigens. P. gingivalis is an important pathogen in a well-established model of mucosal infection, periodontal disease, and its fimbrillin subunit was selected since it has been cloned and sequenced. Furthermore, P. gingivalis fimbrillin domains involved in adherence and in the immune response have been determined. Recombinant S. gordonii strains have been generated that express biologically active domains of fimbrillin and have shown that they are able to generate fimbrillin-specific immune response in rats following oral colonization as well as after parenteral immunization. Rats infected with P. gingivalis were selected as a model of mucosal infection in which to study the early steps in the disease process, namely adherence and colonization, since it is well characterized and provides a useful model to assess in vivo efficacy of a genetically engineered commensal organism producing factors which interfere with virulence. Therefore, studies are proposed to generate recombinant strains of S. gordonii able to either secrete or surface express important fimbrillin peptides, and capable of modulating P. gingivalis infection in a rat model of periodontal disease. Such genetically engineered strains of S. gordonii expressing fimbrillin peptides may be used as a vaccine against P. gingivalis infection, and as a model to study this novel approach to vaccines for other mucosal infections. The model can also be used for evaluating the utility of continuously expressed biologically active molecules by commensal organisms, directed to block colonization and other key early stages in the pathogenesis of mucosal infections.