Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

炭疽致死毒素诱导病理生理学的遗传学修饰

基本信息

批准号：
7690580
负责人：
Kenneth Alan Bradley
金额：
$ 38.68万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-22 至 2009-07-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690580
关键词：
Address Animals Anthrax disease Antigens Automobile Driving Bacillus anthracis Blood Vessels Bone Marrow Transplantation Candidate Disease Gene Cells Chromosome Mapping Clinical Chemistry Congenic Strain Consensus Control Locus Cytolysis Defense Mechanisms Disease Edema Elements Endothelial Cells Event Exhibits Exotoxins Extravasation Functional disorder Gene Chips Genes Genetic Genomics Immune response In Vitro Infection Inflammatory Injection of therapeutic agent Intoxication Knowledge Location Maps Mediator of activation protein Molecular Morbidity - disease rate Mouse Strains Mus Numbers Pathology Pathway interactions Phase Phenotype Plasmids Play Production Proteins Recovery Role Testing Toxin Variant Virulence abstracting anthrax lethal factor base biological adaptation to stress congenic edema factor intravital microscopy macrophage mortality positional cloning receptor binding response tool trait

项目摘要

ABSTRACT Virulence of Bacillus anthracis is associated with the secretion of three plasmid-encoded toxin proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). LF and EF are catalytic moieties that share the receptor-binding subunit, PA. As a result, two binary toxins are formed: lethal toxin (LT) consisting of PA and LF, and edema toxin (ET) consisting of PA and EF. Injection of purified LT into animals induces many of the pathologies associated with fulminate anthrax infection indicating that this toxin plays a significant role in disease. However, there is a lack of consensus about how LT causes these pathologies. In response to LT injection, a rapidly induced phenotype was identified in a congenic strain of mice that has a chromosomal segment of the CAST/EiJ strain on an otherwise C57BL/6J background. Study of this strain will advance the understanding of the mechanism(s) underlying early pathophysiological changes and reveal genetic factors that influence LT induced disease. In addition, this strain recovers from their precipitous decline only to subsequently succumb to LT. The dramatic recovery provides a unique window to investigate host responses that suppress or counter LT induced disease. We propose to study the early LT-response phenotype in these animals. First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., candidate gene, positional cloning, and expression QTL analysis) with the eventual Objective being the identification of the gene(s) responsible for the early phenotype. Second, the pathophysiological mechanism driving the early phenotype, and recovery from it, will be determined by studies that include intravital microscopy, bone marrow transplantation, pathological and clinical chemistry profiles, and gene chip arrays that are focused on recovery phase, stress response pathways. In summary, the early responding congenic strain will be a powerful tool for: 1) identifying genetic factors that regulate sensitivity to LT, 2) elucidating the pathophysiological mechanisms associated with early LT-induced events, and 3) revealing defense mechanisms that are employed by the host in response to LT.

抽象的炭疽芽孢杆菌的毒力与三种质粒编码的毒素蛋白的分泌有关：保护性抗原（PA），致死因子（LF）和水肿因子（EF）。 LF和EF是共享的催化部分宾夕法尼亚州的受体结合亚基。结果，形成了两种二元毒素：由PA组成的致命毒素（LT）和LF，以及由PA和EF组成的水肿毒素（ET）。将纯化的LT注入动物会引起许多与触及炭疽感染相关的病理表明，这种毒素在疾病。但是，关于LT如何引起这些病理的共识缺乏共识。响应LT 注射，在具有染色体的小鼠的先天性菌株中鉴定出快速诱导的表型在其他C57BL/6J背景上，铸件/EIJ应变的段。研究这种菌株将推动了解早期病理生理变化的基本机制并揭示遗传因素这会影响LT诱导的疾病。此外，这种菌株从其急剧下降中恢复了随后屈服于LT。戏剧性的恢复提供了一个独特的窗口来调查主机响应抑制或反LT诱导疾病。我们建议研究这些早期的LT响应表型动物。首先，控制早期灵敏度的定性性状基因座（QTL）将由免费绘制最终目标的方法（即候选基因，位置克隆和表达QTL分析）是负责早期表型的基因的鉴定。其次，病理生理推动早期表型及其恢复的机制将由包括插入显微镜，骨髓移植，病理和临床化学谱以及基因芯片集中于恢复阶段的阵列，应力响应途径。总而言之，早期响应先天性菌株将是一个有力的工具：1）确定调节对LT敏感性的遗传因素，2）阐明与早期LT诱导的事件相关的病理生理机制，3）揭示主机对LT采用的防御机制。