Clinical

临床

• 批准号: 8026694
• 负责人: James P. Nataro
• 金额: $ 49.51万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026694
• 关键词: 5 year old; Address; African; Archives; Area; Asia; Bacteria; Behavior; Biological Markers; Case Management; Cessation of life; Child; Clinical; Collaborations; Complex; Country; DNA; Databases; Diarrhea; Disease; Enteral; Etiology; Fatal Outcome; Feces; Foundations; Freezing; Functional disorder; Funding; Genes; Genome; Genomics; Human; IL8 gene; In Vitro; Infection; Inflammation; Institutes; Interleukin-10; Investigation; Knowledge; Laboratories; Lactoferrin; Life; Maryland; Multicenter Studies; Nucleic Acids; Organism; Outcome; Pathogenesis; Patients; Pilot Projects; Predisposition; Research; Research Personnel; Risk Factors; Role; Sampling; Science; Shigella; Single Nucleotide Polymorphism; Site; Specimen; Study Subject; Testing; Texas; Tissues; Tumor necrosis factor receptor 11b; Universities; Work; authority; microbiome; pathogen; sample collection

Diarrheal diseases are a major killer of children under the age of 5 years (U5) around the worid. Despite this long-recognized association, the precise causes of severe disease remain enigmatic. In an ongoing multisite study of diarrhea in U5 children, the PI will generate a priceless archive of bacterial isolates, fecal nucleic acids and frozen stools themselves from up to 14,000 cases and matched controls. We will leverage this unparalleled set of specimens, in the context of outstanding laboratory investigations into enteric pathogenesis, to address longstanding and critically important research questions. This work will be organized in 3 specific aims. Aim 1. Host genomic biomarkers associated with severe outcome in enteric disease. We will leverage our extensive database and specimen collection to determine the importance of single nucleotide polymorphisms (SNPs) previously associated with diarrhea, including IL-8, IL-10, lactofen'in, and osteoprotegerin genes. We will score these SNPs in host DNA from stool samples and correlate these findings with presence of severe diarrhea and death in the study database. Aim 2. Bacterial interaction in Diarrheal Disease. Most pathogenesis research examines the behavior of a single organism in pure culture, yet the real worid comprises innumerable interactions among living organisms. Our extensive laboratory expertise in pathogenesis allows us to formulate hypothesis-driven questions about the roles of inter-bacterial interaction in the study subjects. Aim 3. Pathogenomics of Shigella species. We will work with the University of Maryland Institute for Genome Sciences to perform the most comprehensive genomic study of Shigella strains ever performed, leveraging the availability of clinically characterized strains. Preliminary studies have revealed certain previously unsuspected genes that are more common among Shigella isolates from Kenyan patients who died of their disease. The association of these genes with severe diarrhea will be tested. This study will advance our knowledge of the most diarrhea cases in U5 subjects.

腹泻病是世界各地5岁以下儿童（U 5）的主要杀手。 尽管这种长期公认的联系，严重疾病的确切原因仍然是个谜。在一项正在进行的U 5儿童腹泻多点研究中，PI将从多达14，000例病例和匹配的对照中生成细菌分离株，粪便核酸和冷冻粪便本身的无价档案。我们将利用这组无与伦比的标本，在肠道发病机制的优秀实验室调查的背景下，解决长期存在的和至关重要的研究问题。这项工作将分为三个具体目标。目标1.与肠道疾病严重结局相关的宿主基因组生物标志物我们将利用广泛的数据库和样本收集来确定先前与腹泻相关的单核苷酸多态性（SNP）的重要性，包括IL-8、IL-10、乳芬素和护骨素基因。我们将对来自粪便样本的宿主DNA中的这些SNP进行评分，并将这些发现与研究数据库中严重腹泻和死亡的存在相关联。目标二。腹泻病中的细菌相互作用。大多数发病机制研究考察的是纯培养中单个有机体的行为，然而真实的世界是由无数生物体之间的相互作用组成的。我们在发病机理方面的广泛实验室专业知识使我们能够制定关于细菌间相互作用在研究对象中的作用的假设驱动问题。目标3。志贺氏菌属的致病基因组学。我们将与马里兰州大学基因组科学研究所合作，利用临床特征菌株的可用性，对志贺氏菌菌株进行有史以来最全面的基因组研究。初步研究揭示了某些以前未被怀疑的基因，这些基因在死于该病的肯尼亚患者的志贺氏菌分离株中更为常见。这些基因与严重腹泻的关联将被检测。这项研究将提高我们对U 5受试者中大多数腹泻病例的认识。