Integrated Analysis of Microbial and Genomic data in Obstructive Lung Disease (I AM GOLD) Study

阻塞性肺疾病（I AM GOLD）研究中微生物和基因组数据的综合分析

• 批准号: 10017311
• 负责人: LAURENCE HUANG
• 金额: $ 75.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017311
• 关键词: Acute Pneumonia; Address; Aging; Automobile Driving; Bacteria; Biological Markers; Biology; Cause of Death; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Data; Development; Diagnostic radiologic examination; Disease Progression; Enrollment; Exposure to; Gammaproteobacteria; Gene Expression; Genomics; Goals; HIV; HIV Infections; HIV therapy; Human; Immune; Immune response; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; International; Intervention; Lung diseases; Microbe; Multicenter Studies; Obstructive Lung Diseases; Outcome; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pneumonia; Population; Populations at Risk; Precision therapeutics; Pseudomonadaceae; Pseudomonas; Pulmonary Emphysema; Resistance; Respiratory physiology; Risk; Sampling; San Francisco; Smoking; Spirometry; Stable Disease; Structure; Subgroup; Testing; Therapeutic Intervention; Thoracic Radiography; Time; Uganda; Work; X-Ray Computed Tomography; acute infection; airway inflammation; base; biomass fuel; chest computed tomography; detector; disorder risk; disorder subtype; dysbiosis; functional decline; genomic data; genomic signature; high risk; host microbiome; lung injury; metabolome; microbial; microbial community; microbial genomics; microbiome; microbiome analysis; mortality; pathogen; pathogenic bacteria; respiratory microbiome; respiratory microbiota; small airways disease; transcriptome

Project Summary/Abstract Patients with HIV are at increased risk for chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. In this proposal, our long-term goal is to identify the mechanisms underlying the increased risk of COPD with HIV infection. Our central hypothesis is that enhanced Th17 driven inflammation and chronic Gammaproteobacteria-dominated airway microbiota interact to contribute to obstructive lung disease in HIV+ individuals. This hypothesis is based on the following evidence. First, we have found in HIV- uninfected COPD patients that a genomic signature of Th17 driven airway inflammation marks a COPD subgroup with functional small airway disease, which is thought to precede emphysema. Second, Th17 driven inflammation, a pathway classically thought to defend against bacteria, is enhanced in the airways of HIV+ patients. Third, our group has shown that amongst Ugandan HIV+ patients with pneumonia, a population at higher risk for lung function decline, there are subgroups characterized by distinct lower airway microbial communities with differing immune responses. One subgroup had Pseudomonadaceae-dominated airway microbiota and inflammatory gene expression. Gammaproteobacteria, which includes Pseudomonas, are commonly found in COPD and, as with Th17 inflammation, are associated with emphysema. Thus, the Pseudomonadaceae-dominant pneumonia subgroup may be at higher risk for developing chronic disease in the setting of continued dysbiosis and low level Th17 driven chronic inflammation. Our proposed specific aims will use existing and newly collected samples from our international multi-center study of HIV-associated COPD, I AM OLD (Inflammation, Aging, Microbes and Obstructive Lung Disease), in which HIV+ participants in Uganda and San Francisco are enrolled at the time of acute pneumonia and followed longitudinally. Aim 1 will identify the airway microbial communities and inflammatory gene expression markers at the time of acute infection that are associated with subsequent incident COPD and lung function decline in HIV. Aim 2 will identify the airway microbial communities and inflammatory gene expression markers during chronic stable disease that are enhanced in HIV+COPD compared to participants without COPD (HIV+COPD-). In Aim 3 we will perform integrative analyses of the airway microbiome, microbial and human transcriptome, metabolome and lung radiographic changes in HIV+COPD. We anticipate the following outcomes: 1) identification of the predominant airway microbiome-host response interactions associated with HIV+COPD in two international at- risk populations, 2) identification of metabolome alterations associated with specific microbial communities and inflammatory responses in HIV+COPD, 3) delineation of the range of radiographic abnormalities associated with microbiome-host response interactions in HIV+COPD. We expect these outcomes to have a positive impact, providing a new understanding of the biology underlying the enhanced risk for COPD amongst the HIV- infected population which could direct therapeutic interventions.

项目总结/文摘