Immunodominant Stress Proteins of Porphyromonas gingivalis

牙龈卟啉单胞菌的免疫显性应激蛋白

• 批准号: 7523092
• 负责人: DENNIS E LOPATIN
• 金额: $ 39.89万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7523092
• 关键词: Adult; Affinity; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigen Presentation; Arterial Fatty Streak; Arteriosclerosis; Bacteria; Bacterial Antigens; Blood Circulation; Blood Vessels; Cell Surface Receptors; Cells; Chlamydia; Chronic; Chronic Disease; Communicable Diseases; Diagnostic; Disease; Foam Cells; Genomics; Gingivitis; Goals; Grant; Health; Heat shock proteins; Heat-Shock Proteins 90; Helicobacter Infections; Homologous Gene; IL8 gene; Immune response; Immunization; Immunodominant Antigens; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Laboratories; Lead; Legionella; Lesion; Leukocytes; Ligands; Lipoprotein Receptor; Literature; Longitudinal Studies; Mediating; Michigan; Microbe; Modality; Modeling; Molecular Chaperones; Natural Immunity; Nature; Oral health; Periodontal Diseases; Periodontitis; Porphyromonas gingivalis; Process; Production; Proteins; Proteomics; Recruitment Activity; Reporting; Role; Sampling; Serum; Signal Transduction; Systemic disease; TLR4 gene; Testing; Tissues; Toll-like receptors; Veins; Work; Yersinia; chemokine receptor; design; disorder control; human disease; in vivo; interest; mRNA Expression; man; microbial; microorganism; novel strategies; novel therapeutics; oral bacteria; pathogen; protective effect; receptor; receptor expression; research study; response; scavenger receptor; small molecule; stress protein

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.

描述（由申请人提供）：伴侣蛋白或热休克蛋白存在于从细菌到人类的所有细胞中，并且是自然界中最高度保守和免疫显性的分子之一。最初被认为促进蛋白质的三维组装，但越来越清楚的是，这些分子具有涉及对多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炎症性肠病、军团菌、耶尔森氏菌、衣原体和幽门螺杆菌感染以及动脉硬化等疾病。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全身性疾病的机制，并制定针对这些疾病的药物治疗策略。我们发现，在一组牙龈炎受试者中，牙周病原体牙龈卟啉单胞菌的 HSP90 同源物 (HtpG) 抗体水平升高与更好的口腔健康相关。在我们目前的资助期间，我们已经证明 HtpG 具有诱导免疫调节活性的能力，类似于其他与慢性传染病相关的细菌的伴侣。在牙周炎中，牙龈卟啉单胞菌 HtpG 将产生抗体的细胞募集到病变部位，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 存在于循环系统和 CVD 粥样斑块中，可诱导泡沫细胞形成，这是动脉粥样硬化斑块形成的重要步骤。 HtpG 抗体可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作用。该应用将 1) 表征 P. gingivalis HtpG 体外独特的受体介导的免疫调节活性； 2) 通过显微切割、基因组/蛋白质组学方法证明在牙周炎和血管组织中具有相同的体内活性； 3) 将血清抗体与驱动该过程的分子的存在相关联。这样的示范将为牙周炎和牙周炎相关全身性疾病的新治疗和诊断方式铺平道路。 项目叙述：在细胞中产生特定类别蛋白质（称为伴侣蛋白）的分子在某些情况下可能参与疾病过程。了解这种情况发生的方式可以帮助治疗由长期未解决的牙周炎引起的慢性疾病。