Molecular basis of host immune responses to periodontal disease

宿主对牙周病免疫反应的分子基础

• 批准号: 15209062
• 负责人: YAMAMOTO Kenji
• 金额: $ 31.95万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15209062/
• 关键词: Infectious disease; Tumor; Dentistry; Immunology; Pharmacology; Periodontal disease; Porphyromonas gingivalis; Proteases; ジンジバリス菌; 免疫応答; ジンジパイン; カテプシンE; エンドソーム・リソソーム系; 歯周病治療薬

Chronic periodontitis is an inflammatory disease associated with bacteria. Recent epidemiological studies have suggested a link between chronic periodontal disease and an increased risk of cardiovascular disease. Gingipains are cysteine proteinases produced by Porphyromonas gingivalis, a Gram-negative anaerobic bacterium associated with chronic periodontitis and implicated in a wide range of virulence of the bacterium, which are now classified into two types of proteinases, Arg-gngipains (Rgps) and Lys-gingipain (Kgp). On the other hand, cathepsin E is an endolysosomal aspartic proteinase predominantly expressed in immune system cells and implicated in immune defense responses against bacterial infection. As the development of periodontitis is a result of the balance between bacterial infection and host defense, it is of particular importance for us to investigate pathophysiological roles of these proteinases in periodondal disease and to develop new promising agents for periodontitis … More therapy. The findings obtained through this work are as follows : (1)we first purified a 660-kDa cell associated gingipain complex existing as a homodimer of two catalytically active monomers comprising the catalytic and adhesin domains of Rgp and Kgp and found the complex to play an important role in evasion of host defense mechanisms and host tissue breakdown. (2)We designed and synthesized for the first time a series of peptide analogs able to inhibit Rgp or Kgp on the basis of the cleavage site specificity of histatins by each enzyme. Among this series of compounds, we found that KYT-1 and KYT-36 had the most potent and selective inhibitory activities of Rgp and Kgp, respectively, and that they are useful in assessing the pathophysiological functions of each enzyme. (3)We provide evidence that the proteolytic cleavage of apoB-100, the only protein component of LDL particles, by Rgp is crucial for the promotion of atherosclerosis by P.gingivalis infection. (4)We demonstrate that cathepsin E plays an essential role in immune defense against invaded microorganisms including P.gingivalis. Less

慢性牙周炎是与细菌有关的炎症性疾病。最近的流行病学研究表明，慢性牙周疾病与心血管疾病的风险增加之间有联系。牙龈蛋白是由牙龈卟啉单胞菌产生的半胱氨酸蛋白酶，牙龈牙龈蛋白酶是一种与慢性牙周炎相关的革兰氏阴性厌氧菌细菌，并暗示了各种细菌病毒，现在已分类为两种类型的蛋白酶，Arg-Gnipains（RGPS）（RGPS）和Lys-gyipain（lys-gyipain）。另一方面，组织蛋白酶E是一种主要在免疫系统细胞中表达的内溶性天冬氨酸蛋白酶，在针对细菌感染的免疫防御反应中暗示。由于牙周炎的发展是细菌感染与宿主防御之间平衡的结果，因此我们对这些蛋白酶在周期疾病中的病理生理作用并为牙周炎开发新的承诺剂……更多的治疗是非常重要的。通过这项工作获得的发现如下：（1）我们首先纯化了与两个催化活性单体的同型二聚体相关的660 kDa细胞相关的gingipain复合物，该催化活性单体完成了RGP和KGP的催化和粘合剂结构域，并发现了综合体在宿主防御机制和宿主组织的进化中起重要作用。 （2）我们首次设计和合成了一系列肽类似物可以根据每种酶的裂解位点特异性抑制RGP或KGP。在这一系列化合物中，我们发现KYT-1和KYT-36分别具有RGP和KGP的最潜力和选择性抑制活性，并且它们在评估每种酶的病理生理功能方面非常有用。 （3）我们提供的证据表明，通过RGP，APOB-100的蛋白水解裂解是LDL颗粒的唯一蛋白质成分，对于吉维利斯感染促进动脉粥样硬化至关重要。 （4）我们证明，组织蛋白酶e在防御包括吉利亚病毒在内的侵略微生物的免疫防御中起着至关重要的作用。较少的

项目成果

実験医学 22, 213-219

实验医学 22, 213-219

• 发表时间: 2004
• 作者: 山本健二;岩田淳一
• 通讯作者: 岩田淳一

Tsukuba T., et al.: "Association of cathepsin E deficiency of atopic dermatitis"J.Biochem.. 134. 893-902 (2003)

Tsukuba T.等人：“组织蛋白酶E缺乏与特应性皮炎的关联”J.Biochem..134.893-902(2003)

Kadowaki T., et al.: "Suppression of virulence of Porphyromonas gingivalis by potent inhibitors specific for gingipains"Current Protein Peptide Sci.. 4. 451-458 (2003)

Kadowaki T.等人：“通过针对牙龈疼痛的有效抑制剂抑制牙龈卟啉单胞菌的毒力”Current Protein Peptide Sci.. 4. 451-458 (2003)

A functional virulence complex composed of gingipains, adhesins, and lipopolysaccharides shows high affinity to host cells and matrix proteins and escapes recogniyion by host immune systems.

由牙龈蛋白酶、粘附素和脂多糖组成的功能性毒力复合物对宿主细胞和基质蛋白具有高亲和力，并且逃避宿主免疫系统的识别。

• 发表时间: 2005
• 期刊: Infect.Immun. 73
• 作者: R.Takii;et al.
• 通讯作者: et al.

山本 健二: "臨床検査47"医学書院. 849-858 (2003)

Kenji Yamamoto：“临床检查 47”Igaku Shoin 849-858 (2003)。