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: 7474675
• 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/7474675
• 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; Condition; 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; 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; Students; TLR2 gene; TLR4 gene; Tertiary Protein Structure; Training; Training Programs; Transplantation; Universities; base; career; enteroaggregative Escherichia coli; experience; 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）：本提案描述了一个为期5年的培训计划，用于发展外科学术生涯。主要研究者（PI）是一名助理教授，在马里兰州大学和约翰霍普金斯大学儿科外科联合任职。总体目标是PI扩大其科学武器库，长期目标是成为独立的科学研究者。James Nataro医学博士，博士将是他的主要导师;他是肠聚集性大肠杆菌的发病机理、基因组学、分子流行病学和诊断方面的专家。杆菌他培养了许多博士后研究员和研究生。位于巴尔的摩的马里兰州大学，包括其疫苗开发中心和粘液生物学研究中心，为基础科学研究和多学科合作提供了极好的环境。研究项目的描述如下：胆汁淤积定义为很少或没有胆汁流动，是一种常见的疾病，与儿童和成人的严重并发症有关，有时甚至是毁灭性的并发症。已知胆汁淤积与肠道屏障功能衰竭有关;肠道的细菌和其他物质进入循环并引发全身炎症反应，导致多个器官受损。如果胆汁淤积进展不受控制，肝或多脏器移植可能是必要的生存。不幸的患者可能无法存活到移植。目前尚不清楚为什么有些患者比其他患者更容易发生严重的并发症。我们观察到两种近交系小鼠C57 BL 6/cJ（B6）和A/J之间胆总管结扎（CBDL）后全身炎症反应和结局的差异，表明遗传贡献。B6小鼠比AJ小鼠病得更重，死得更快。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产生的发病率和死亡率。首先，我们将测量肠道通透性，并在CBDL后对两种菌株进行细菌易位研究。其次，我们将确定TLR 2和TLR 4信号通路发挥什么作用。第三，我们将确定NOD 1和NOD 2信号通路发挥什么作用。在这种小鼠模型中注意到的差异背后的机制和基因可能以相同的方式参与人类，并可能最终为识别胆汁淤积后更频繁和更严重的脓毒症风险的个体提供基础。