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（由申请人提供）：COPD 是一种与 HIV 相关的肺部疾病，是发病和死亡的主要原因。 HIV 相关的 COPD（HIV+COPD）的机制尚不完全清楚，但 HIV 特异性或 HIV 增强因素已被了解。研究表明，相当大比例的 HIV+COPD 发生在非吸烟者中，并且该疾病通常比未感染 HIV 的人患 COPD 的年龄更早，因此我们的研究将调查广泛的潜在机制和一套全面的机制。我们将使用由肺炎康复者组成的 IHOP 队列，因为研究表明这些患者肺功能和慢性阻塞性肺病的严重下降风险特别高。以端粒缩短为特征的炎症和功能性 PBMC 缺陷会导致 HIV+ 个体肺功能的更大程度下降，而微生物易位可能会导致这一过程。我们的初步数据表明，PBMC 端粒长度缩短和血浆升高的趋势明显。在我们的 IHOP 队列中，IL-6 水平与 COPD 相关 目标 1：检验 PBMC 和 BAL 中端粒长度短和/或端粒长度/端粒酶活性 (TL/TA) 比率低与患病率增加相关的假设。目标 2：检验血浆和 BAL 中免疫激活和炎症的选定标志物与 COPD 患病率增加相关的假设。目标 3：验证目标中确定的标志物。在正在进行的多中心、前瞻性 HIV+ 队列中对 1 和 2 进行研究，并检验以下假设：所识别的标记物与肺功能（FEV1 和 FEV1/FVC）的更大下降相关，并且作为次要目标，与 DLco 和发育的更大下降相关COPD 的目标 1 和 2 将利用现有的超过 300 名 HIV+ 受试者的旧金山 IHOP 队列，我们​​将对 70 名患有 COPD 的受试者进行横断面、巢式病例对照研究。对 140 名没有 COPD 的受试者进行分析，分析门诊研究访问中储存的血液的端粒长度、TL/TA 以及 12 种免疫激活和炎症标记物，这些标记物是根据未感染 HIV 的人群中与 COPD 的关系而选择的。 ，调整年龄、性别和吸烟情况并进行多重比较，并得出一组候选生物标志物进行前瞻性验证。作为一个子目标，我们还将分析 BAL 中的这些标志物并将其与来自血液的比较。目标 3 将使用旧金山、西雅图和乌干达坎帕拉正在进行的 IHOP 队列，对 50 名患有和不患有 COPD 的 HIV+ IHOP 受试者进行连续支气管镜检查。在完成肺炎治疗（基线）后 3 个月以上开始分析目标 1 和 2 中确定的标志物，然后每年一次直至研究完成，并将这些测量值与肺功能测试和胸部 CT 进行关联同一时间点，加强目标 1 和 2 中的因果推论，并为未来的治疗干预试验奠定基础（摘要结束）。