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Integrated Multi-omics of Melioidosis

类鼻疽的综合多组学

基本信息

批准号：
10204943
负责人：
Sina A Gharib
金额：
$ 75.83万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-23 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204943
关键词：
Acute Pneumonia Address Antimicrobial Resistance Bacteria Bacterial Infections Bioinformatics Biological Biological Process Blood Blood specimen Burkholderia pseudomallei Candidate Disease Gene Cells Cessation of life Clinical Collaborations Communities Complement Data Data Set Development Diagnosis Diagnostic Disease Early identification Environmental Exposure Exposure to Genes Genetic Determinism Genetic Transcription Genetic Variation Host Defense Mechanism Human Human Genetics Immune Immune response Immunotherapy In Vitro Infection Inflammatory Response Ingestion Inhalation Investigation Knowledge Leukocytes Measures Melioidosis Messenger RNA Metabolic Pathway MicroRNAs Molecular Molecular Profiling Outcome Pathogenesis Pathogenicity Pathway interactions Patients Plasma Play Predisposition Process Prognosis Proteins Proteomics Public Health Research Research Personnel Resources Risk Role Sepsis Soil Technology Testing Therapeutic Vaccine Design Vaccines Work adverse outcome aptamer base combat computer framework differential expression exome sequencing experience experimental study high risk improved in vitro Assay in vivo Model innovation interest metabolomics mortality multidimensional data multiple omics neglect new therapeutic target next generation novel novel strategies peripheral blood predictive signature prevent prognostic prognostic signature risk stratification septic patients tool transcriptome sequencing transcriptomics vaccine development

项目摘要

PROJECT SUMMARY Melioidosis, a tropical infection commonly manifesting as acute pneumonia and sepsis in humans, is caused by the Gram-negative Tier 1 select agent Burkholderia pseudomallei and represents a global public health threat with an estimated 165,000 cases and 89,000 deaths annually worldwide (an overall mortality rate of 54%). Unfortunately numerous barriers exist to decreasing the burden of melioidosis including lack of an effective vaccine, difficulty diagnosing and identifying high-risk patients, and challenges in treatment due to extensive antimicrobial resistance of B. pseudomallei and lack of targeted immunotherapies. While work to date spotlights the promise of the application of advanced technologies to melioidosis and identifies several targets for further study, an incomplete understanding of the pathogenic mechanisms underlying host susceptibility and outcome impedes efforts to prevent, diagnose, risk-stratify and treat this infection. The overall hypothesis of this project is that by generating and integrating a rich compendium of multidimensional data – transcriptomic, proteomic, and metabolomic – from circulating immune cells and blood of patients with melioidosis and selected controls, it is possible to identify fundamental biological pathways and processes activated during melioidosis. Such comprehensive data, complemented by targeted in vitro experiments, are desperately needed to inform the design of vaccines, diagnostics, prognostics and therapeutics to combat this infectious threat. This hypothesis will be tested in the following aims: 1) Identify biological pathways that distinguish melioidosis from other causes of sepsis; 2) Define biological processes and develop prognostic signatures that predict death in melioidosis; and 3) Validate the function of key genes and pathways in human cells infected with B. pseudomallei in vitro. This application leverages the investigators’ scientific and clinical expertise in melioidosis, cutting edge bioinformatics capacity in transcriptomics, proteomics, and metabolomics both as independent domains and integrated together, and a rich clinical and biological dataset of over 5,000 septic patients due to melioidosis or to other infections. The successful completion of this project will yield an unprecedented granular overview of mechanisms leading to melioidosis and the molecular signatures associated with clinical outcomes, while also providing a unique resource to the scientific community to guide further research into this important but neglected disease.

项目摘要类鼻疽是一种热带感染，通常表现为人类急性肺炎和败血症，革兰氏阴性1级选择性病原体类鼻疽伯克霍尔德氏菌，代表全球公共卫生全世界每年估计有165，000例病例和89，000例死亡（总死亡率为 54%）。不幸的是，在减少类鼻疽的负担方面存在许多障碍，包括缺乏一种治疗方法。有效的疫苗，诊断和识别高风险患者的困难，以及治疗方面的挑战， B的广泛耐药性。假鼻疽和缺乏靶向免疫疗法。虽然工作，日期突出了应用先进技术治疗类鼻疽的前景，并确定了几个进一步研究的目标，对宿主致病机制的不完全理解易感性和结果阻碍了预防、诊断、风险分层和治疗这种感染的努力。的这个项目的总体假设是，通过生成和整合一个丰富的多维数据-转录组学，蛋白质组学和代谢组学-来自循环免疫细胞和血液患者，类鼻疽和选定的对照，有可能确定基本的生物学途径和过程在类鼻疽病期间激活。如此全面的数据，再加上有针对性的体外实验，迫切需要为疫苗、诊断、预后和治疗的设计提供信息来应对这一问题传染性威胁这一假设将在以下目标中进行测试：1）确定生物学途径，将类鼻疽与其他脓毒症原因区分开来; 2）定义生物学过程并制定预后预测类鼻疽死亡的特征;和3）确定人类中关键基因和途径的功能感染B.类鼻疽体外培养。该应用程序利用了研究人员的科学和临床在类鼻疽方面的专业知识，在转录组学、蛋白质组学和代谢组学方面的尖端生物信息学能力作为独立的领域和集成在一起，以及超过5，000的丰富的临床和生物数据集，由于类鼻疽病或其他感染引起的败血症患者。该项目的成功完成将产生导致类鼻疽的机制和分子特征的前所未有的颗粒概述与临床结果相关，同时也为科学界提供了一个独特的资源，进一步研究这种重要但被忽视的疾病。