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: 7303543
• 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/7303543
• 关键词: Adult; Appointment; Bacteria; Bacterial Translocation; Baltimore; Basic Science; Bile fluid; Biliary; Biology; Blood Circulation; Child; Cholestasis; Common bile duct structure; Condition; Diagnosis; Doctor of Medicine; Doctor of Philosophy; Environment; Extrahepatic; Failure; Genes; Genetic; Genomics; Goals; Human; Impairment; Inbred Strains Mice; Individual; Inflammatory Response; Inflammatory disease of the intestine; Interdisciplinary Study; Intestines; Joints; Ligation; Liver; Maryland; Measures; Mentors; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mus; Natural Immunity; Obstruction; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Patients; Pediatric Surgical Procedures; Permeability; Play; Postdoctoral Fellow; Principal Investigator; Program Development; Recovery; Research; Research Personnel; Research Project Grants; Risk; Role; Secondary to; Sepsis; Signal Pathway; Students; TLR2 gene; TLR4 gene; Training; Training Programs; Transplantation; Universities; base; career; enteroaggregative Escherichia coli; mortality; mouse model; professor; 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(由申请者提供)：这份建议书描述了一项为期5年的外科学术生涯发展培训计划。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学部门的联合任命的助理教授。总体目标是让PI扩大他的科学武器库，长期目标是成为一名独立的科学调查员。詹姆斯·纳塔罗医学博士将是他的主要导师；他是肠聚集性大肠杆菌的发病机制、基因组学、分子流行病学和诊断方面的专家。培养了众多博士后研究员和研究生。位于巴尔的摩的马里兰大学包括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一流的环境。对该研究项目的描述如下：胆汁淤积被定义为胆汁很少或没有流动，是一种常见的情况，与儿童和成人的严重、有时是毁灭性的并发症有关。众所周知，胆汁淤积症与肠道屏障功能衰竭有关；来自肠道的细菌和其他物质进入血液循环，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，肝脏或多脏器移植可能是生存所必需的。不太幸运的患者可能无法存活到移植。目前尚不清楚为什么一些患者比其他患者更容易出现严重的并发症。我们观察到C57BL6/CJ(B6)和A/J两个近交系小鼠在胆总管结扎(CBDL)后全身炎症反应和结果的差异，表明遗传因素有关。与AJ小鼠相比，B6小鼠的病情更重，死亡更早。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信号通路所起的作用。第三，我们将确定NOD1和NOD2信号通路所起的作用。在这个小鼠模型中注意到的差异背后的机制和基因可能在人类中以相同的方式参与，并最终可能为识别胆汁淤积症后更频繁和更严重的脓毒症风险的个体提供基础。