H. hepaticus: the pathogenesis of IBD

肝螺杆菌：IBD 的发病机制

• 批准号: 6922880
• 负责人: DAVID B SCHAUER
• 金额: $ 24.65万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922880
• 关键词: Crohn' s disease; Helicobacter; T lymphocyte; bacterial cytopathogenic effect; bacterial genetics; cytokine; disease /disorder etiology; electroporation; enzyme linked immunosorbent assay; flow cytometry; fluorescence microscopy; gene targeting; genetically modified animals; immunocytochemistry; inflammatory bowel diseases; laboratory mouse; leukocyte activation /transformation; macrophage; microarray technology; pathologic process; polymerase chain reaction; southern blotting; tissue /cell culture; ulcerative colitis; virulence

DESCRIPTION (provided by applicant): Idiopathic inflammatory bowel disease (IBD) is a debilitating condition with no known etiology. The pathogenesis of IBD has been studied using targeted gene mutant (knockout) mice that develop chronic intestinal inflammation, which resembles human IBD. It has been shown in several of these knockout mouse models, including T cell receptor alpha beta (TCR alpha beta), interleukin-2 (IL-2), and IL-10 knockout mice, that germ-free conditions protect against the development of IBD. It does not appear that resident intestinal microbiota are sufficient to trigger disease in these animals, but experimental infection with an emerging group of murine bacterial pathogens called enterohepatic Helicobacter species is sufficient to cause IBD. To better understand the pathogenesis of disease in these models, we propose to elucidate the mechanisms by which enterohepatic Helicobacter species cause IBD in knockout mice. Although the adaptive immune system is important in the pathogenesis of IBD, knockout mice lacking adaptive immunity are also susceptible to Helicobacter-associated IBD. For this reason, our proposed studies focus on interactions between enterohepatic Helicobacter species and the innate immune system. Studies will be carried out with Helicobacter hepaticus, the most well characterized enterohepatic Helicobacter species. We and our collaborators have recently determined the complete genome sequence of H. hepaticus ATCC 51449. Taking advantage of the genome sequence, we will identify and characterize candidate bacterial virulence determinants, and generate isogenic mutant strains to test in culture with murine intestinal epithelial cell monolayers and murine macrophages, and in vivo with selected knockout mouse models. These studies will test the hypothesis that discrete bacterial virulence determinants in enterohepatic Helicobacter species elicit proinflammatory responses from the innate immune system, which in the absence of a properly regulated adaptive immune system, lead to IBD. It is hoped that these studies will lead to the development of new strategies for the treatment and the prevention of IBD.

描述（由申请人提供）：特发性炎症性肠病（IBD）是一种使人衰弱的疾病，病因不明。使用靶向基因突变（敲除）小鼠研究了 IBD 的发病机制，这些小鼠会出现类似于人类 IBD 的慢性肠道炎症。在其中一些敲除小鼠模型中，包括 T 细胞受体 αβ (TCR αβ)、白细胞介素-2 (IL-2) 和 IL-10 敲除小鼠模型中显示，无菌条件可防止细菌的发展。炎症性肠病。肠道常驻微生物群似乎不足以引发这些动物的疾病，但实验性感染一种新兴的鼠类细菌病原体（称为肠肝螺杆菌）足以引起 IBD。为了更好地了解这些模型中疾病的发病机制，我们建议阐明肠肝螺杆菌在基因敲除小鼠中引起 IBD 的机制。尽管适应性免疫系统在 IBD 的发病机制中很重要，但缺乏适应性免疫的基因敲除小鼠也容易感染螺杆菌相关的 IBD。因此，我们提出的研究重点是肠肝螺杆菌与先天免疫系统之间的相互作用。将对肝螺杆菌进行研究，肝螺杆菌是特征最清楚的肠肝螺杆菌种。我们和我们的合作者最近确定了肝螺杆菌 ATCC 51449 的完整基因组序列。利用该基因组序列，我们将鉴定和表征候选细菌毒力决定簇，并生成同基因突变株以在小鼠肠上皮细胞单层培养物中进行测试和鼠巨噬细胞，以及体内选定的基因敲除小鼠模型。这些研究将检验这样的假设：肠肝螺杆菌种中离散的细菌毒力决定因素会引起先天免疫系统的促炎症反应，在缺乏适当调节的适应性免疫系统的情况下，会导致 IBD。希望这些研究将有助于制定治疗和预防 IBD 的新策略。