Immunosuppressive Proteins Produced by Oral Pathogens

口腔病原体产生的免疫抑制蛋白

基本信息

批准号：
7024557
负责人：
BRUCE J SHENKER
金额：
$ 30.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2008-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Over the past several years, significant progress has been made in understanding of the etiology and pathogenesis of periodontal diseases. Nevertheless, the nature and contribution of the immune system to these disorders remain unclear. The basic hypothesis is that the immune system plays a primary role to minimize and/or prevent infection. Furthermore, the application posits that immunoregulatory abnormalities contribute to the pathogenesis of and susceptibility to periodontal disease. In this regard, the prior investigations have demonstrated that Fusobacterium nucleatum and Treponema denticola produce immunosuppressive proteins (ISPs). The fundamental hypothesis of the proposed studies is that periodontal pathogens produce ISPs that mediate local and/or systemic immunosuppression, thereby enhancing their own virulence and/or that of other opportunistic microorganisms. The plan is to focus this investigation on the F. nucleatum (Fip) and T. denticola (Sip) ISP which has been shown to induce human lymphocytes to arrest in the mid G 1 phase of the cell cycle. Moreover, the preliminary studies determined each ISP is composed of two subunits. The objectives of this application are to define the events responsible for ISP-induced G1 arrest and to determine the relationship between structure and function of the ISP subunits. The study is composed of four Specific Aims: 1) To determine the molecular mechanism(s) responsible for F. nucleatum (Fip) and 7' denticola (Sip) ISP-induced G1 arrest in human lymphocytes; 2) To determine if G1 arrest is irreversible resulting in activation of the G1 checkpoint and the apoptotic cascade; 3) To determine if Fip exists and functions as a heterodimer and examine the individual role of Fip A and Fip B in the induction of G 1 arrest; and 4) To determine if the two peptides that comprise the ISP of 7' denticola (Sip) are encoded by separate genes and, if so, to determine the functional role of each peptide.

描述（由申请人提供）：在过去的几年中，很重要在理解病因和发病机理方面取得了进展牙周疾病。然而，免疫的性质和贡献这些疾病的系统尚不清楚。基本的假设是免疫系统起着最小化和/或防止感染的主要作用。此外，应用假定免疫调节异常有助于对牙周疾病的发病机理和易感性。在这方面，先前的调查表明梭杆菌核和treponema牙本质产生免疫抑制蛋白（ISP）。拟议研究的基本假设是牙周病原体产生介导局部和/或全身免疫抑制的ISP，从而增强自己的毒力和/或其他机会主义的毒力微生物。该计划是将这项研究集中在F. nucleatum上（FIP）和T. denticola（SIP）ISP，已显示出诱导人类淋巴细胞在细胞周期的G 1期间停滞。而且，初步研究确定每个ISP由两个亚基组成。这此应用程序的目标是定义负责的事件 ISP诱导的G1逮捕并确定结构与 ISP亚基的功能。该研究由四个特定目的组成：1）确定负责F. nubleatum（FIP）和的分子机制和 7'Denticola（SIP）ISP诱导的人类淋巴细胞中的G1停滞； 2）确定如果G1逮捕是不可逆的，导致G1检查点的激活和凋亡级联； 3）确定FIP是否存在并起作用异二聚体并检查FIP A和FIP B在诱导中的个体作用 G 1逮捕； 4）确定两个肽是否包含ISP 7'Denticola（SIP）由单独的基因编码，如果是的，则确定每个肽的功能作用。