Clostridium difficile Cooperative Research Center

描述（由申请人提供）：密歇根大学肠道研究调查网络合作研究中心（UM ERIN CRC）由一个综合的多学科研究团队组成，他们在细菌发病机理，微生物生态学，免疫学，人类遗传学，传染病，生物信息学，临床医学和老年病学方面具有专业知识。为了充分利用团队的专业知识，他们目前的研究兴趣和过去的研究成果，UM ERIN CRC将集中精力研究艰难梭菌引起的抗生素相关性结肠炎。艰难梭菌感染（CDI）是一种重新出现的传染病，是负责显著的发病率和死亡率。然而，尽管CDI具有重要意义，但我们对这种感染的发病机制的了解仍存在重大差距。为了解决这些差距，umerin CRC将开展三个项目。在第一个项目中，将进行临床调查，收集临床标本（粪便、血液和人类DNA）和艰难梭菌菌株，这些标本来自无症状感染者和初始发作或不同严重程度的复发性CDI患者。艰难梭菌菌株将被遗传表征，以了解细菌多样性/进化在疾病过程中的作用。这些信息将用于开发快速单核苷酸多态性分型方案，以帮助快速诊断和分子流行病学。第二个项目将利用临床标本和临床菌株来确定本地微生物群在CDI中的作用。关于肠道微生物生态学和CDI的具体假设将在我们在实验室组中激活的新型小鼠模型中进行测试。这个项目的最后一部分涉及到艰难梭菌在食物中产生孢子/细菌的能力与CDI发病机制之间的关系。来自第一个项目的临床菌株的孢子生物学将被表征，并使用小鼠模型测试变体的持续能力和致病能力。还将构建和表征产孢途径的靶向突变体。第三个项目将利用CDI的临床标本和小鼠模型来表征宿主反应在CDI发病机制中的作用。先天和适应性免疫反应在介导临床疾病和易感性中的作用将通过检查来自人类临床病例和小鼠模型的样品中的反应和生物标志物来确定。这些综合项目将增加我们对艰难梭菌疾病的了解，并为这一日益重要的病原体带来新的诊断和治疗方式。

DESCRIPTION (provided by applicant): The University of Michigan Enterics Research Investigational Network Cooperative Research Center (UM ERIN CRC) is composed of an integrated, multidisciplinary team of investigators who have expertise in bacterial pathogenesis, microbial ecology, immunology, human genetics, infectious diseases, bioinformatics, clinical medicine and geriatrics. To leverage the expertise of the assembled team, their current research interests and past research accomplishments, the UM ERIN CRC will focus its efforts on the study of antibiotic-associated colitis due to Clostridium difficile. C. difficile infection (CDI) is a re-emerging infectious disease that is responsible for significant morbidity and mortality. However, despite the significance of CDI, there are major gaps in our knowledge of the pathogenesis of this infection. To address these gaps, the UM ERIN CRC will carry out three projects. In the first project a clinical survey will be conducted to collect clinical specimens (feces, blood and human DNA) and C. difficile strains from asymptomatically infected individuals and patients with initial episodes or recurrent CDI of varying severity. The C. difficile strains will be genetically characterized to understand the role of bacterial diversity/evolution in the disease process. This information will be used to develop a rapid single-nucleotide polymorphism typing scheme to aid in rapid diagnosis and molecular epidemiology. The second project will utilize the clinical specimens and clinical strains to determine the role of the indigenous microbiota in CDI. Specific hypotheses regarding gut microbial ecology and CDI will be tested in a novel murine model that we have activated in our laboratory group. The last portion of this project involves examination of the relationship between the ability of C. difficile to sporulate/germ in ate and the pathogenesis of CDI. The spore biology of the clinical strains from the first project will be characterized and variants tested for the ability to persist and cause disease using the murine model. Targeted mutants of the sporulation pathway will also be constructed and characterized. The third project will leverage the clinical specimens and the murine model of CDI to characterize the role of the host response in CDI pathogenesis. The role of innate and adaptive immune responses in mediating clinical disease and susceptibility will be determined by examining responses and biomarkers in samples from human clinical cases and the murine model. These integrated projects will increase our understanding of C. difficile disease and lead to novel diagnostic and therapeutic modalities for this increasingly important pathogen.