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，他们在细菌发病机制，微生物生态学，免疫学，人类遗传学，传染病，生物信息学，临床医学和老年医学方面具有专业知识。为了利用组装团队的专业知识，他们目前的研究兴趣和过去的研究成果，UM ERIN CRC将集中精力研究由艰难梭菌引起的结肠炎相关性结肠炎。C.艰难梭菌感染（CDI）是导致显著发病率和死亡率的重新出现的感染性疾病。然而，尽管CDI的意义，有重大差距，我们的知识，这种感染的发病机制。为了弥补这些差距，UM ERIN 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C。来自无症状感染个体和具有不同严重程度的初始发作或复发性CDI的患者的艰难菌株。梭将对艰难梭菌菌株进行遗传表征，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土著微生物群在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实验室组激活的新型小鼠模型中进行测试。本课题的最后一部分涉及到对C语言能力之间关系的研究。难以形成孢子/胚芽的细菌以及CDI的发病机制。将对第一个项目的临床菌株的孢子生物学进行表征，并使用鼠模型检测变体的持续存在和致病能力。还将构建和表征孢子形成途径的靶向突变体。第三个项目将利用临床标本和CDI小鼠模型来表征宿主反应在CDI发病机制中的作用。先天性和适应性免疫应答在介导临床疾病和易感性中的作用将通过检查来自人临床病例和鼠模型的样品中的应答和生物标志物来确定。这些综合项目将增加我们对C.艰难梭菌疾病，并导致新的诊断和治疗方式，这种日益重要的病原体。

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.