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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.

项目总结