The Role of Genetics in Innate Immunity Following Cholestasis

遗传学在胆汁淤积后先天免疫中的作用

• 批准号: 7664877
• 负责人: SAMUEL M ALAISH
• 金额: $ 12.69万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7664877
• 关键词: A/J Mouse; Adult; Appointment; Bacteria; Bacterial Translocation; Baltimore; Basic Science; Bile fluid; Biliary; Binding; Biology; Biomedical Research; Blood Circulation; Child; Cholestasis; Common bile duct structure; Cytosol; Diagnosis; Doctor of Medicine; Doctor of Philosophy; Electrical Resistance; Endotoxins; Environment; Epithelial Cells; Extrahepatic; Failure; Genes; Genetic; Genomics; Goals; Histological Techniques; Human; Impairment; Inbred Strains Mice; Individual; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interdisciplinary Study; Intestines; Joints; Lead; Ligation; Lipopolysaccharides; Liver; Maryland; Measures; Mentors; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mus; Muscle; Natural Immunity; Nucleotides; Obstruction; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathologic; Patients; Pediatric Surgical Procedures; Permeability; Phagocytosis; Play; Postdoctoral Fellow; Principal Investigator; Program Development; Recovery; Reporting; Research; Research Personnel; Research Project Grants; Risk; Role; Secondary to; Sepsis; Signal Pathway; Signal Transduction; Signaling Protein; TLR2 gene; TLR4 gene; Tertiary Protein Structure; Training; Training Programs; Transplantation; Universities; base; career; enteroaggregative Escherichia coli; experience; graduate student; insight; mortality; mouse model; professor; programs; tissue culture; vaccine development

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in surgery. The principal investigator (PI) is an Assistant Professor with joint appointments in the Divisions of Pediatric Surgery at the University of Maryland and Johns Hopkins University. The overall objective is for the PI to expand his scientific arsenal with the long-term goal of becoming an independent scientific investigator. James Nataro M.D., Ph.D. will be his primary mentor; he is an expert on the pathogenesis, genomics, molecular epidemiology and diagnosis of enteroaggregative E. coli. He has trained numerous postdoctoral fellows and graduate students. The University of Maryland at Baltimore, which includes its Center for Vaccine Development and the Mucosal Biology Research Center, offers a superb environment for basic science research as well as multidisciplinary collaborations. A description of the research project follows: Defined as little or no bile flow, cholestasis is a common condition associated with significant and sometimes devastating complications in both children and adults. Cholestasis is known to be associated with the failure of intestinal barrier function; bacteria and other substances from the intestine enter the circulation and initiate a systemic inflammatory response which causes impairment of multiple organs. If cholestasis progresses unchecked, liver or multivisceral transplantation may be necessary for survival. Less fortunate patients may not survive to transplantation. It remains unclear why some patients are predisposed to more significant complications than others. We have observed differences in the systemic inflammatory responses and outcome following common bile duct ligation (CBDL) between two inbred mouse strains, C57BL6/cJ (B6) and A/J, suggesting a genetic contribution. The B6 mice become more ill and die sooner than the AJ mice. We hypothesize that the genetic background dictates the degree of intestinal inflammation and permeability, systemic inflammatory response and resultant morbidity and mortality following extrahepatic biliary obstruction. First, we will measure intestinal permeability and perform bacterial translocation studies on the two strains following CBDL. Second, we will determine what role the TLR2 and TLR4 signaling pathways play. Third, we will determine what role the NOD1 and NOD2 signaling pathways play. The mechanism and genes behind the differences noted in this mouse model are likely to participate in the same fashion in humans and may ultimately provide a basis for identifying individuals at risk for more frequent and more severe sepsis followina cholestasis.

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，以发展外科学术生涯。首席研究员（PI）是马里兰大学和约翰霍普金斯大学儿科外科联合任命的助理教授。PI的总体目标是扩大其科学武器库，长期目标是成为一名独立的科学研究者。James Nataro医学博士将是他的主要导师；他是肠聚集性大肠杆菌发病机制、基因组学、分子流行病学和诊断方面的专家。他培养了许多博士后和研究生。马里兰大学巴尔的摩分校包括其疫苗开发中心和粘膜生物学研究中心，为基础科学研究和多学科合作提供了极好的环境。该研究项目描述如下：胆汁淤积症的定义是胆汁很少或没有流动，它是一种常见的疾病，在儿童和成人中都有明显的、有时是毁灭性的并发症。胆汁淤积症与肠屏障功能衰竭有关；肠道中的细菌和其他物质进入循环系统，引发系统性炎症反应，导致多个器官受损。如果胆汁淤积不受控制，肝脏或多脏器移植可能是生存所必需的。不幸的患者可能无法存活到移植。目前还不清楚为什么有些患者比其他人更容易出现严重的并发症。我们观察了两种近交系小鼠C57BL6/cJ （B6）和A/J在胆总管结扎（CBDL）后的全身炎症反应和结果的差异，提示遗传贡献。B6小鼠比AJ小鼠病得更重，死亡也更快。我们假设遗传背景决定了肝外胆道梗阻后肠道炎症和通透性的程度、全身炎症反应以及由此导致的发病率和死亡率。首先，我们将测量肠道通透性，并对CBDL后的两种菌株进行细菌易位研究。其次，我们将确定TLR2和TLR4信号通路的作用。第三，我们将确定NOD1和NOD2信号通路的作用。在这个小鼠模型中发现的差异背后的机制和基因很可能在人类中以同样的方式参与，并可能最终为识别在胆汁淤积后更频繁和更严重的脓毒症风险个体提供基础。