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S GORDONII AS A VECTOR FOR P GINGIVALIS FIMBRILLIN

S GORDONII 作为 P Gingivalis Fimbrillin 的载体

基本信息

批准号：
2897161
负责人：
Ashu Sharma
金额：
$ 18.36万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-20 至 2002-09-19
项目状态：
已结题

项目摘要

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.

描述(改编自调查人员摘要)：广泛的，该项目的长期目标是开发一个连续的产生阻止粘膜感染的生物活性因子。申请人建议开发基因工程菌株共生生物体，戈登链球菌，它表达牙龈卟啉单胞菌fimbrins多肽可阻断粘附性，并诱导保护性免疫反应。具体目标是：(1)进一步鉴定新近开发的表达系统在我们实验室对牙周炎假单胞菌的表面进行了检测。 (2)优化戈登氏链霉菌的分泌系统。生产牙周炎假单胞菌；和(3)对其进行遗传学检测戈登葡萄球菌工程菌株在牙周病大鼠模型中的应用减少牙龈假单胞菌的定植和预防破坏性牙周炎。Gordonii被选中是因为它是一个非致病性共生生物体，普遍存在于人类口腔中空洞，菌株已经经过基因工程，可以表达外源基因抗原。牙龈假单胞菌是一种重要的病原菌。粘膜感染、牙周病及其亚基的模型因为它已经被克隆和测序，所以被选中。此外，P. 牙周炎菌膜蛋白结构域参与粘附性和免疫性已经确定了反应。重组戈登葡萄球菌菌株已经被产生了表达Fimbrin生物活性区域并具有表明它们能够在体内产生苯莫西林特异的免疫反应口服定植和非肠道免疫后的大鼠。选用感染牙龈假单胞菌的大鼠作为大鼠牙周炎模型。感染，研究疾病过程的早期步骤，即坚持和殖民，因为它的特点很好，并提供了一种评估基因工程药物体内疗效的实用模型共生有机体产生干扰毒力的因素。因此，有必要开展重组菌株的研制工作。 Gordonii能够分泌或表面表达重要的膜蛋白多肽，并能够在大鼠模型中调节牙龈假单胞菌感染牙周病。这些经过基因工程改造的戈登氏链球菌表达的fimbrin多肽有可能作为疫苗使用。作为研究这一新方法的模型其他黏膜感染的疫苗。该模型还可用于评价连续表达生物活性的效用分子由共生生物体引导，以阻止殖民和其他粘膜感染发病机制的关键早期阶段。