Inflammation, Aging, Microbes, and Obstructive Lung Disease (I AM OLD) Study

炎症、衰老、微生物和阻塞性肺病 (I AM OLD) 研究

• 批准号: 9257199
• 负责人: ELIZABETH H BLACKBURN
• 金额: $ 72.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257199
• 关键词: Acute Pneumonia; Address; Affect; Age; Aging; Biological Markers; Blood; Blood Banks; Bronchoscopy; Cardiovascular Diseases; Chronic; Chronic Obstructive Airway Disease; Data; Defect; Development; Diagnosis; Disease; Enrollment; Etiology; Foundations; Functional disorder; Future; Goals; HIV; HIV Infections; Immunologic Markers; Immunologics; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Interleukin-6; International; Intervention Trial; Knowledge; Length; Leukocytes; Life; Link; Longitudinal cohort study; Lung diseases; Measurement; Measures; Mediating; Microbe; Morbidity - disease rate; Nested Case-Control Study; Newly Diagnosed; Non-Insulin-Dependent Diabetes Mellitus; Obstruction; Obstructive Lung Diseases; Outpatients; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Plasma; Pneumonia; Population; Prevalence; Prevention; Process; Public Health; Pulmonary Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; RNA; Reporting; Respiratory physiology; Risk; Role; Sampling; San Francisco; Smoking; Structure of parenchyma of lung; Telomerase; Telomere Shortening; Testing; Therapeutic Trials; Time; TimeLine; Toxin; Uganda; Visit; antiretroviral therapy; cancer type; candidate marker; chest computed tomography; cohort; enhancing factor; experience; functional decline; high risk; immune activation; improved; inflammatory marker; lymphocyte proliferation; microbial; monocyte; mortality; non-smoker; novel; novel therapeutic intervention; pathogen; prospective; sex; telomere; trend

 DESCRIPTION (provided by applicant): COPD is an HIV-associated lung disease and a leading cause of morbidity and mortality. The mechanisms underlying HIV-associated COPD (HIV+COPD) are incompletely understood but HIV-specific or HIV-enhanced factors have been suggested as a substantial proportion of HIV+COPD occur in non-smokers and the disease typically develops at an earlier age than COPD in HIV-uninfected individuals. Our study will investigate a wide- range of potential mechanisms and a comprehensive set of biomarkers. We will use our IHOP cohort composed of HIV+ subjects who have recovered from pneumonia as studies indicate that these patients are at an especially high-risk for a greater decline in lung function and COPD. Our central hypothesis is that systemic immune activation and inflammation and functional PBMC defects characterized by shortened telomeres contribute to a greater decline in lung function in HIV+ individuals, and that microbial translocation may contribute to this process. Our preliminary data demonstrate a strong trend for shortened PBMC telomere length and elevated plasma IL-6 levels to be associated with COPD in our IHOP cohort. Aim 1: To test the hypothesis that short telomere length and/or low telomere length/telomerase activity (TL/TA) ratio in PBMCs and BAL are associated with an increased prevalence of COPD. Aim 2: To test the hypothesis that selected markers of immune activation and inflammation in plasma and BAL are associated with an increased prevalence of COPD. Aim 3: To validate the markers identified in Aims 1 & 2 in an ongoing multicenter, prospective HIV+ cohort and to test the hypothesis that the identified markers are associated with a greater decline in lung function (FEV1 and FEV1/FVC) and, as secondary aims, with a greater decline in DLco and development of COPD. Aims 1 & 2 will leverage the existing San Francisco IHOP cohort of >300 HIV+ subjects. We will conduct a cross-sectional, nested case-control study of 70 subjects with COPD and 140 subjects without COPD and analyze banked blood from an outpatient study visit for telomere length, TL/TA, and 12 markers of immune activation and inflammation, selected for their association with COPD in HIV- uninfected populations. We will investigate associations with HIV+COPD, adjusting for age, sex, and smoking and for multiple comparisons, and derive a set of candidate biomarkers to validate prospectively. As a sub-aim, we will also analyze these markers in BAL and compare them to blood from 50 HIV+ IHOP subjects with and without COPD undergoing serial bronchoscopies for an IHOP study. Aim 3 will use the ongoing IHOP cohorts in San Francisco, Seattle, and Kampala, Uganda. We will conduct a longitudinal cohort study of 600 HIV+ subjects recovered from pneumonia and analyze the markers identified in Aims 1 & 2 beginning >3 months after completion of pneumonia treatment (baseline) and then annually until study completion and correlate these measurements with lung function tests and chest CT performed at the same time-points, strengthening the causal inferences in Aims 1 & 2 and setting the foundation for future trials of therapeutic interventions. (End of Abstract)

 描述（由适用提供）：COPD是一种与HIV相关的肺部疾病，是发病率和死亡率的主要原因。尚不完整地理解与HIV相关的COPD（HIV+COPD）的基础机制，但已经提出了HIV特异性或HIV增强因素，因为在非吸烟者中发生了很大一部分HIV+COPD，并且疾病通常在HIV未感染的个体中比COPD更早的年龄发展。我们的研究将研究广泛的潜在机制和一组全面的生物标志物。我们将使用由HIV+受试者组成的IHOP队列，这些受试者从肺炎中恢复过来，因为研究表明这些患者处于尤其高风险，肺功能和COPD的下降较大。我们的中心假设是，以缩短端粒为特征的全身免疫激活，炎症和功能性PBMC缺陷有助于HIV+个体的肺功能下降，而微生物易位可能有助于这一过程。我们的初步数据表明，缩短PBMC端粒长度和IL-6等离子水平升高的趋势与我们的IHOP队列中的COPD相关。目标1：测试以下假设：PBMC和BAL中短的端粒长度和/或低端粒长度/端粒酶活性（TL/TA）比与COPD的患病率的增加有关。目标2：测试以下假设：血浆和BAL中免疫激活和炎症的选定标记与COPD患病率的增加有关。目的3：验证在正在进行的多中心，前瞻性HIV+队列中目标1和2中确定的标记，并检验以下假设：确定的标记与肺功能的较大下降有关（FEV1和FEV1和FEV1/FVC），并且作为次要目标，DLCO和COPD的发展较大。 AIMS 1和2将利用现有的旧金山IHOP队列> 300 HIV+受试者。我们将对70名具有COPD的受试者和140名没有COPD的受试者进行横断面的，嵌套的病例对照研究，并对端粒长度，TL/TA的门诊研究访问，TL/TA和12个Immuno激活和炎症标记，以与HIV未感染的COPD相关性。我们将调查与HIV+COPD的关联，调整年龄，性别和吸烟以及多次比较，并得出一组候选生物标志物，以前瞻性验证。作为一个子AIM，我们还将在BAL中分析这些标记，并将其与有或没有COPD进行连续支气管镜检查的50名HIV+ IHOP受试者的血液进行比较，以进行IHOP研究。 AIM 3将使用位于旧金山的西雅图和乌干达的坎帕拉的IHOP同伙。 We will conduct a longitudinal cohort study of 600 HIV+ subjects recovered from pneumonia and analyze the markers identified in Aims 1 & 2 beginning >3 months after completion of pneumonia treatment (baseline) and then annually until study completion and correlate these measurements with lung function tests and chest CT performed at the same time-points, strengthening the catusal inferences in Aims 1 & 2 and setting the foundation for future trials治疗干预措施。 （抽象的结尾）