Epithelium, dendritic cells, and Clostridium difficile associated colitis

上皮、树突状细胞和艰难梭菌相关结肠炎

基本信息

  • 批准号:
    7887611
  • 负责人:
  • 金额:
    $ 41.53万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-05-01 至 2015-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Clostridium difficile, an etiologic agent for pseudomembranous colitis, accounts for a quarter cases of antibiotic-associated diarrhea. With the recent emergence of hypervirulent strains, the incidence of C. difficile infection (CDI) has increased significantly in both North America and Europe, causing lengthy hospitalization, substantial morbidity and mortality. CDI is thought to be mainly mediated by exotoxins TcdA and TcdB, which glucosylate low molecular mass GTPase of the Rho family, leading to massive fluid secretion, acute inflammation, and necrosis of the colonic mucosa. Our long-term goal is to understand the mechanisms mediating intestinal inflammation in C. difficile infection and to utilize this knowledge for the design of better immune interventions in order to reduce the incidence of CDI and severity of the disease. The interaction of intestinal epithelial cells (IECs) with intestinal antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages, in the gut orchestrates mucosal immune homeostasis and inflammatory response. Our objective is to elucidate the immune response of IECs and intestinal DCs after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction. To achieve this objective, we will test several working hypotheses: 1) C. difficile toxin-intoxicated IECs are capable of mobilizing and activating DCs; 2) In severe cases of CDI, C. difficile toxins can cross a severely damaged intestinal barrier and further activate DCs and macrophages; and 3) proinflammatory cytokine TNF-a synergizes with the toxins to induce apoptosis of IECs, thus exacerbating tissue destruction and enterocolitis. By testing these hypotheses, we expect to gain a better understanding of not only the underlying mechanisms by which C. difficile toxins induce severe enterocolitis, but also the role of IEC-DC interaction in the onset and development of intestinal inflammatory diseases in general. We believe that such an understanding will help us to design better immune interventions against CDI and other intestinal inflammatory diseases. PUBLIC HEALTH RELEVANCE: Clostridium difficile is the most common cause of hospital-acquired antibiotic-associated diarrhea and the etiologic agent of pseudomembranous colitis, the most severe intestinal inflammation. The diseases are in mainly caused by toxins secreted by the bacteria. The goal of this project is to elucidate the immune response of the intestinal epithelial cells (the first line of cells encountering the toxins) and intestinal dendritic cells (the immune cells regulating intestinal inflammatory response) after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction. We believe the study will help us to design better immune interventions against C. difficile infection and other intestinal inflammatory diseases.
描述(由申请方提供):艰难梭菌是伪膜性结肠炎的病原体,占腹泻相关性腹泻病例的四分之一。随着近年来超强毒株的出现,C.在北美和欧洲,艰难梭菌感染(CDI)显著增加,导致住院时间长、发病率和死亡率高。CDI被认为主要由外毒素TcdA和TcdB介导,它们使Rho家族的低分子量GTPase葡萄糖基化,导致大量液体分泌、急性炎症和结肠粘膜坏死。我们的长期目标是了解C.艰难梭菌感染,并利用这些知识设计更好的免疫干预措施,以减少CDI的发病率和疾病的严重程度。肠上皮细胞(IEC)与肠抗原呈递细胞(APC)(如树突状细胞(DC)和巨噬细胞)在肠道中的相互作用协调粘膜免疫稳态和炎症反应。我们的目的是阐明IEC和肠道DC在暴露于C.艰难梭菌毒素,并确定其相互作用的性质,引发肠道炎症和组织破坏。为了实现这一目标,我们将测试几个工作假设:1)C。艰难梭菌毒素中毒的IEC能够动员和激活DC; 2)在严重的CDI病例中,C.艰难梭菌毒素可以穿过严重受损的肠屏障并进一步激活DC和巨噬细胞;和3)促炎细胞因子TNF-α与毒素协同作用以诱导IEC的凋亡,从而加剧组织破坏和小肠结肠炎。通过验证这些假设,我们不仅希望更好地了解C。艰难梭菌毒素诱导严重的小肠结肠炎,而且IEC-DC相互作用在一般肠道炎性疾病的发生和发展中的作用。我们相信,这样的理解将有助于我们设计更好的免疫干预措施来对抗CDI和其他肠道炎症性疾病。 公共卫生相关性:艰难梭菌是医院获得性腹泻的最常见原因,也是伪膜性结肠炎(最严重的肠道炎症)的病原体。这些疾病主要由细菌分泌的毒素引起。本课题的目的是阐明肠道上皮细胞(接触毒素的第一道防线细胞)和肠道树突状细胞(调节肠道炎症反应的免疫细胞)在暴露于C.艰难梭菌毒素,并确定其相互作用的性质,引发肠道炎症和组织破坏。我们相信,这项研究将有助于我们设计更好的免疫干预措施,对C。艰难梭菌感染和其他肠道炎症性疾病。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)

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Hanping Feng其他文献

Hanping Feng的其他文献

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{{ truncateString('Hanping Feng', 18)}}的其他基金

Characterization of neutralizing antitoxins and epitopes in Clostridium difficile patients
艰难梭菌患者中和抗毒素和表位的特征
  • 批准号:
    10549285
  • 财政年份:
    2020
  • 资助金额:
    $ 41.53万
  • 项目类别:
Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies
通过分泌多特异性单域抗体的工程益生菌布拉酵母菌预防诺如病毒和艰难梭菌胃肠炎
  • 批准号:
    10540345
  • 财政年份:
    2020
  • 资助金额:
    $ 41.53万
  • 项目类别:
Preventing norovirus and Clostridium difficile gastroenteritis by engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies
通过分泌多特异性单域抗体的工程益生菌布拉酵母菌预防诺如病毒和艰难梭菌胃肠炎
  • 批准号:
    10320907
  • 财政年份:
    2020
  • 资助金额:
    $ 41.53万
  • 项目类别:
Characterization of neutralizing antitoxins and epitopes in Clostridium difficile patients
艰难梭菌患者中和抗毒素和表位的特征
  • 批准号:
    10319522
  • 财政年份:
    2020
  • 资助金额:
    $ 41.53万
  • 项目类别:
Probiotic yeast secreting single-domain antibodies to prevent Clostridium difficile and Campylobacter jejuni disease
益生菌酵母分泌单域抗体来预防艰难梭菌和空肠弯曲菌疾病
  • 批准号:
    10364713
  • 财政年份:
    2019
  • 资助金额:
    $ 41.53万
  • 项目类别:
Probiotic yeast secreting single-domain antibodies to prevent Clostridium difficile and Campylobacter jejuni disease
益生菌酵母分泌单域抗体来预防艰难梭菌和空肠弯曲菌疾病
  • 批准号:
    10584482
  • 财政年份:
    2019
  • 资助金额:
    $ 41.53万
  • 项目类别:
A Novel Humanized Tetra-specific Antibody against Clostridium difficile Infection
一种抗艰难梭菌感染的新型人源化四特异性抗体
  • 批准号:
    10432036
  • 财政年份:
    2017
  • 资助金额:
    $ 41.53万
  • 项目类别:
A Novel Humanized Tetra-specific Antibody against Clostridium difficile Infection
一种抗艰难梭菌感染的新型人源化四特异性抗体
  • 批准号:
    9362547
  • 财政年份:
    2017
  • 资助金额:
    $ 41.53万
  • 项目类别:
Toxemia and systemic disease in Clostridium difficile infection
艰难梭菌感染的毒血症和全身性疾病
  • 批准号:
    8664002
  • 财政年份:
    2013
  • 资助金额:
    $ 41.53万
  • 项目类别:
Development of Vaccines against Clostridium difficile Infection
艰难梭菌感染疫苗的研制
  • 批准号:
    7903007
  • 财政年份:
    2010
  • 资助金额:
    $ 41.53万
  • 项目类别:

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初级保健中用于治疗急性下呼吸道感染的大剂量抗生素吸入器
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