Immunodominant Stress Proteins of Porphyromonas gingivalis

描述(申请人提供)：伴侣或热休克蛋白存在于从细菌到人类的所有细胞中，是自然界中最高度保守和免疫优势的分子之一。最初被认为是为了促进蛋白质的三维组装，现在越来越清楚的是，这些分子具有涉及对各种微生物的免疫反应的功能。此外，研究表明，对应激蛋白的保护性反应可能参与控制IBD、军团菌、耶尔森氏菌、衣原体、幽门螺杆菌感染和动脉硬化等疾病。这项工作的长期目标是阐明伴侣参与牙周炎和牙周炎相关系统性疾病的机制，并开发这些疾病的药物治疗策略。我们已经证明，牙周病原体P.gigivalis的HSP90同源(HtpG)抗体水平的升高与牙周炎受试者更好的口腔健康有关。在我们目前的资助期间，我们已经证明了HtpG具有诱导免疫调节活性的能力，类似于来自与慢性传染病相关的其他细菌的伴侣。在牙周炎中，牙龈假单胞菌HtpG招募产生抗体的细胞到病变处，并上调白细胞和血管细胞上的趋化因子受体，从而导致持续的组织破坏。HtpG在循环和CVD动脉粥样硬化中被发现，并能诱导泡沫细胞形成，这是动脉粥样硬化斑块形成的重要步骤。抗HtpG抗体下调白细胞和静脉细胞中IL-8的产生，并可能减轻牙周炎的炎症效应。这一应用将1)在体外表征牙龈假单胞菌HtpG独特的受体介导的免疫调节活性；2)通过显微切割、基因组/蛋白质组学方法在牙周炎和血管组织中展示相同的活性；3)将血清抗体与驱动这一过程的分子的存在联系起来。这一演示将为牙周炎和牙周炎相关系统性疾病的新治疗和诊断方法铺平道路。 项目旁白：在某些情况下，在细胞中产生一种特殊类型的蛋白质的分子称为伴侣蛋白，可以参与疾病过程。了解这种情况的发生方式可以导致对慢性疾病的治疗，这些疾病是长期、未解决的牙周炎的结果。

DESCRIPTION (provided by applicant): Chaperones or heat shock proteins are found in all cells from bacteria to man and are among the most highly conserved and immunodominant molecules in nature. Originally thought to facilitate the three dimensional assembly of proteins it has become increasingly clear that these molecules have functions involving the immune response to a variety of microorganisms. In addition it has been shown that protective response to stress proteins may be involved in control of diseases like IBD, Legionella, Yersinia, Chlamydia and H. pylori infections and arteriosclerosis. The long-term goals of this work is to deliniate the mechanisms of chaperone involvement in periodontitis and periodontitis-related systemic disease and to develop strategies for medicinal treatment for those diseases. We have shown that elevated levels of antibodies to the HSP90 homolog (HtpG) of the periodontal pathogen P. gingivalis were found associated with better oral health in a group of gingivitis subjects. During our current grant we have demonstrated HtpG has the ability to induce immunomodulatory activity similar to chaperones from other bacteria associated with chronic infectious diseases. In periodontitis P. gingivalis HtpG recruits antibody producing cells to the lesion and upregulates chemokine receptors on both leukocytes and vascular cells contributing to the continuning tissue destruction. HtpG is found in circulation and CVD atheromas and can induce foam cell formation, an important step in atherosclerotic plaque formation. Antibodies to HtpG downregulate IL-8 production in both leukocytes and vein cells and may mitigate the inflammatory effects in periodontitis. This application will 1) chacterize the distinct receptor-mediated immunomodulatory activities of P. gingivalis HtpG in vitro; 2) demonstrate the same activity in vivo in periodontitis and vascular tissue by microdisection, genomic/proteomic approaches; 3) correlate serum antibodies to the presence of the molecules that drive this process. Such a demonstration will prepare the way for novel therapeutic and diagnostic modalities for both periodontitis and periodontitisrelated systemic diseases. PROJECT NARATIVE: Molecules that produce a particular class of proteins proteins in cells called chaperones can become involved in disease processes under some circumstances. Understanding the way this happens can lead to treatments for chronic diseases that are the result of long-lasting, unresolved periodontitis.