Genetic Determinants of Host Susceptibility to Pulmonary Anthrax

宿主对肺炭疽易感性的遗传决定因素

基本信息

批准号：
7477723
负责人：
Jagjit S Yadav
金额：
$ 22.96万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7477723
关键词：
Acute Lung Injury Address Animals Anthrax Attack Anthrax disease Anthrax exposure Bacillus anthracis Bacillus anthracis spore Bacteremia Breathing Candidate Disease Gene Chromosomes, Human, Pair 11 Clinical Communicable Diseases Complex Computer Simulation Cutaneous Cytolysis Deterioration Development Disease Disease Outcome Disease susceptibility Exhibits Exposure to Family member Fatal Outcome Future Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Germination Goals Host resistance Human Immune Immune response In Vitro Inbred Mouse Inbred Strains Mice Individual Infection Inhalation Exposure Injection of therapeutic agent Integration Host Factors Investigation Kinesin Laboratory Animals Lethal Dose 50 Link Lung Mass Vaccinations Measures Mediating Modeling Molecular Mus Natural Resistance Nature Pathogenesis Pathology Patients Pattern Play Population Populations at Risk Predisposition Prevention Process Prophylactic treatment Quantitative Trait Loci Reproduction spores Research Resistance Resistance to infection Risk Assessment Role Route Septic Toxemia Symptoms Time Vaccination Variant Virulence Virulence Factors anthrax lethal factor base biothreat design flu gastrointestinal human population genetics improved in vivo innovation interest macrophage mortality novel novel therapeutics pathogen pressure response

项目摘要

DESCRIPTION (provided by applicant): Due to the existing biothreat of B. anthracis, and its potential to cause high mortality when weaponized for inhalation exposure, there is an increasing interest in understanding the pathogenesis and treatment of pulmonary anthrax. Pulmonary anthrax is usually biphasic in nature, with an insidious onset of flu-like symptoms, followed by rapid deterioration characterized by the development of acute lung injury, often leading to a fatal outcome. There is a critical need to better comprehend the host mechanisms involved in B. anthracis infection of the lung and the pathogenesis of pulmonary anthrax caused by inhalation of anthrax spores. In addition to the known host macrophage sensitivity to anthrax lethal toxin, unknown host factors influence B. anthracis infection and virulence. Our long-term goal is to understand the genetic factors of host susceptibility to B. anthracis spore-induced pulmonary anthrax. Our hypothesis is that inter-individual variability in the development of pulmonary anthrax from exposure to B. anthracis is controlled by host genetic factors that influence the survival time during the infection process. We propose to use multiple inbred mouse strains to investigate this hypothesis. The Specific Aims are: 1) to determine inter-strain differences between inbred mice for survival time during the development of B. anthracis spore-induced pulmonary anthrax, and 2) to identify quantitative trait loci (QTLs) with linkage to survival time of mice developing B. anthracis spore-induced pulmonary anthrax and in silico analysis of the QTLs for initial assessment of the candidate genes. This R21 effort will constitute an initial progress toward a full future effort to thoroughly characterize novel host genetic determinants, and assess functional significance of specific candidate genes to understand host-mediated mechanisms and develop new therapeutics for the treatment of pulmonary anthrax. The proposed research will help understand the genetic basis of inter-individual susceptibility to pulmonary anthrax. The scientific developments could redirect or strengthen first-response and continuing clinical approaches to a pulmonary anthrax biothreat situation, as well as the improvement of risk assessment through the identification of "at risk" populations.

描述（由申请人提供）：由于炭疽芽孢杆菌的现有生物治疗及其在吸入暴露武器时引起高死亡率的潜力，因此对理解肺炭疽病的发病机理和治疗的兴趣越来越高。肺炭疽本质上通常是双相性的，具有阴险的流感样症状，其次是快速恶化的特征，其特征是急性肺损伤的发展，通常导致致命的结果。迫切需要更好地理解与肺链球菌感染有关的宿主机制，以及由吸入炭疽孢子引起的肺炭疽病的发病机理。除了已知的宿主巨噬细胞对炭疽致死毒素的敏感性外，未知的宿主因子还会影响炭疽芽孢杆菌感染和毒力。我们的长期目标是了解宿主对炭疽芽孢杆菌孢子诱导的肺炭疽病的易感性的遗传因素。我们的假设是，从暴露于嗜血杆菌的肺炭疽病发育中的个体间变异性受宿主遗传因素的控制，这些因素会影响感染过程中的生存时间。我们建议使用多种近交小鼠菌株来研究这一假设。具体目的是：1）确定植物小鼠之间的应变间差异在炭疽芽孢杆菌孢子诱导的肺炭疽病的生存时间和2）中确定定量性状基因座（QTL），并链接到小鼠生存时间开发炭疽芽孢杆菌孢子诱导的肺炭疽病，并在对QTLS的硅分析中，以评估候选基因。这种R21的工作将构成最初的进步，以彻底表征新型宿主遗传决定因素，并评估特定候选基因的功能意义，以了解宿主介导的机制并为治疗肺炭疽病的治疗提供新的疗法。拟议的研究将有助于了解个体间易感性肺炭疽病的遗传基础。科学的发展可以重定向或加强第一回应，并通过识别“处于风险”人群来改善风险评估，并持续临床。