IMMUNODOMINANT STRESS PROTEINS OF P. GINGIVALIS

牙龈卟啉单胞菌的免疫显性应激蛋白

基本信息

  • 批准号:
    6754507
  • 负责人:
  • 金额:
    $ 31.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-04-01 至 2006-05-31
  • 项目状态:
    已结题

项目摘要

Studies performed in our laboratory implicate the Porphyromonas gingivalis HtpG stress protein, the prokaryotic homologue of Hsp90, in the etiology of periodontal disease. We have reported that elevated levels of anti-Hsp90 antibodies, concomitant with P. gingivalis colonization, are associated with periodontal health. Transcription of HtpG message was also found to be upregulated 7-10-fold in P. gingivalis obtained from diseased subgingival plaque. There is a precedence for Hsp90 homologues contributing to pathogenicity of other microorganisms. Immunity to a single Hsp90 epitope of Candida albicans has been demonstrated to confer protection against systemic candidiasis. Studies performed by our laboratory have revealed that P. gingivalis HtpG has a significant degree of homology with human Hsp90, but remains clearly distinct from other HtpG proteins due to its unique C-terminal region. We have found that HtpG is localized to P. gingivalis membranes and extracellular vesicles, and that it cross-reacts with other prokaryotic and eukaryotic Hsp90 homologues. Our findings suggest that HtpG is readily accessible to participate in host cellular invasion processes, as well as to interfere with normal host cell functions one P. gingivalis enters the host cytoplasmic compartment. Transfection of KB cells with the P. gingivalis htpG gene stimulates IL-8 production by these cells. This application proposes to extend our investigations into the role that molecular mimicry by HtpG plays in the pathogenicity of P. gingivalis. Previous studies of other pathogenic microorganisms which appear to use the Hsp90 homologue as a virulence factor have been purely descriptive. Our application is unique in that while will propose to evaluate the role of HtpG in adherence and invasion mechanisms, we also propose to elucidate novel pathogenic mechanism(s) by which microorganisms such as P. gingivalis utilize molecular mimicry to disrupt normal eukaryotic cell function(s). Since the most clearly defined eukaryotic Hsp90-mediated mechanisms involved signal transduction pathways, these will be the primary foci of our investigations. The hypothesis to be tested in this study is: 1) HtpG plays a role in adherence and invasion of host cells; and 2) once internalized, signal transduction mechanisms mediated by Hsp90/TRAP1 within eukaryotic cells are disrupted by the HtpG of P. gingivalis through molecular mimicry. This leads to disruption of normal inflammatory cytokine responses to microbial invasion by P. gingivalis and other oral microorganisms.
我们实验室进行的研究表明,牙龈卟啉单胞菌 HtpG 应激蛋白(Hsp90 的原核同源物)与牙周病的病因有关。 我们已经报道,随着牙龈卟啉单胞菌定植,抗 Hsp90 抗体水平升高与牙周健康相关。 还发现从患病龈下菌斑获得的牙龈卟啉单胞菌中 HtpG 信息的转录上调了 7-10 倍。 Hsp90 同源物优先促进其他微生物的致病性。已证明对白色念珠菌的单个 Hsp90 表位的免疫力可提供针对系统性念珠菌病的保护。我们实验室进行的研究表明,牙龈卟啉单胞菌 HtpG 与人类 Hsp90 具有显着程度的同源性,但由于其独特的 C 末端区域,与其他 HtpG 蛋白仍然明显不同。 我们发现 HtpG 定位于牙龈卟啉单胞菌膜和细胞外囊泡,并且它与其他原核和真核 Hsp90 同源物发生交叉反应。 我们的研究结果表明,当牙龈卟啉单胞菌进入宿主细胞质区室时,HtpG 很容易参与宿主细胞侵袭过程,并干扰正常宿主细胞功能。 用牙龈卟啉单胞菌 htpG 基因转染 KB 细胞会刺激这些细胞产生 IL-8。本申请旨在扩展我们对 HtpG 分子模拟在牙龈卟啉单胞菌致病性中所起作用的研究。 先前对似乎使用 Hsp90 同源物作为毒力因子的其他病原微生物的研究纯粹是描述性的。 我们的应用的独特之处在于,虽然我们将评估 HtpG 在粘附和侵袭机制中的作用,但我们还建议阐明牙龈卟啉单胞菌等微生物利用分子拟态破坏正常真核细胞功能的新致病机制。 由于最明确的真核 Hsp90 介导机制涉及信号转导途径,因此这些将是我们研究的主要焦点。本研究要检验的假设是:1)HtpG在宿主细胞的粘附和侵袭中发挥作用; 2) 一旦内化,真核细胞内 Hsp90/TRAP1 介导的信号转导机制就会被牙龈卟啉单胞菌的 HtpG 通过分子模拟破坏。 这导致正常炎症细胞因子对牙龈卟啉单胞菌和其他口腔微生物入侵的反应被破坏。

项目成果

期刊论文数量(0)
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DENNIS E LOPATIN其他文献

DENNIS E LOPATIN的其他文献

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{{ truncateString('DENNIS E LOPATIN', 18)}}的其他基金

SALIVARY FACTORS AND DENTAL/MEDICAL RISK FACTORS
唾液因素和牙科/医疗风险因素
  • 批准号:
    6296265
  • 财政年份:
    1999
  • 资助金额:
    $ 31.74万
  • 项目类别:
SALIVARY FACTORS AND DENTAL/MEDICAL RISK FACTORS
唾液因素和牙科/医疗风险因素
  • 批准号:
    6104771
  • 财政年份:
    1999
  • 资助金额:
    $ 31.74万
  • 项目类别:
SALIVARY FACTORS AND DENTAL/MEDICAL RISK FACTORS
唾液因素和牙科/医疗风险因素
  • 批准号:
    6296270
  • 财政年份:
    1998
  • 资助金额:
    $ 31.74万
  • 项目类别:
SALIVARY FACTORS AND DENTAL/MEDICAL RISK FACTORS
唾液因素和牙科/医疗风险因素
  • 批准号:
    6270308
  • 财政年份:
    1998
  • 资助金额:
    $ 31.74万
  • 项目类别:
SALIVARY FACTORS AND DENTAL/MEDICAL RISK FACTORS
唾液因素和牙科/医疗风险因素
  • 批准号:
    6238442
  • 财政年份:
    1997
  • 资助金额:
    $ 31.74万
  • 项目类别:
IMMUNODOMINANT STRESS PROTEINS OF P GINGIVALIS
牙龈卟啉单胞菌的免疫显性应激蛋白
  • 批准号:
    2132234
  • 财政年份:
    1996
  • 资助金额:
    $ 31.74万
  • 项目类别:
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
  • 财政年份:
    1996
  • 资助金额:
    $ 31.74万
  • 项目类别:
IMMUNODOMINANT STRESS PROTEINS OF P. GINGIVALIS
牙龈卟啉单胞菌的免疫显性应激蛋白
  • 批准号:
    6634634
  • 财政年份:
    1996
  • 资助金额:
    $ 31.74万
  • 项目类别:
IMMUNODOMINANT STRESS PROTEINS OF P. GINGIVALIS
牙龈卟啉单胞菌的免疫显性应激蛋白
  • 批准号:
    6900249
  • 财政年份:
    1996
  • 资助金额:
    $ 31.74万
  • 项目类别:
IMMUNODOMINANT STRESS PROTEINS OF P. GINGIVALIS
牙龈卟啉单胞菌的免疫显性应激蛋白
  • 批准号:
    6516473
  • 财政年份:
    1996
  • 资助金额:
    $ 31.74万
  • 项目类别:

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