Inflammation, Aging, Microbes, Obstructive Lung Disease and Diffusion Abnormalities (I AM OLD-DA) Study

炎症、衰老、微生物、阻塞性肺病和扩散异常 (I AM OLD-DA) 研究

• 批准号: 10798953
• 负责人: LAURENCE HUANG
• 金额: $ 5.31万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798953
• 关键词: Abbreviations; Acute; Address; Age; Aging; Biological Markers; Biological Specimen Banks; Biology; Blood; Blood Banks; Blood specimen; Bronchoalveolar Lavage; Bronchodilator Agents; Bronchoscopy; C-reactive protein; Carbon Monoxide; Cell Aging; Cessation of life; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Coagulation Process; Cytomegalovirus; Data; Diffusion; Enrollment; Fibrin; Foundations; Future; Goals; HIV; HIV Infections; High Prevalence; Immunologic Markers; Inflammation; Interferons; Interleukin-6; Intervention Studies; Lead; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Lung; Lung diseases; Lymphocyte Activation; Macrophage Activation; Measurement; Measures; Mediating; Microbe; Morbidity - disease rate; Names; Obstructive Lung Diseases; Participant; Pathogenicity; Pathway interactions; Persons; Phenotype; Pneumonia; Population; Prevalence; Protein Secretion; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Research Design; Risk Factors; Specimen; Spirometry; Telomerase; Testing; Therapeutic Intervention; Time; Uganda; Virus Diseases; Work; biomarker panel; chemokine; clinically significant; co-infection; cohort; immune activation; improved; inflammatory marker; insight; lung injury; monocyte; mortality; novel; novel marker; novel therapeutics; peripheral blood; personalized medicine; prevent; pulmonary function; response; telomere

ABSTRACT Chronic obstructive pulmonary disease (COPD) is an HIV-associated lung disease and a leading cause of morbidity and mortality, and its clinical significance is increasing as the HIV+ population ages worldwide. Despite this, our understanding of the mechanisms underlying HIV+ COPD is limited but both HIV-related and COPD- specific mechanisms are hypothesized. An improved understanding is critical for developing new therapies to treat or prevent this growing problem. This study builds upon a novel, established multinational (US and Uganda) cohort of HIV+ persons. The study measured selected markers of immune activation, inflammation, lung injury, and cellular aging in both blood and lung specimens. The study also performed lung function testing and examined the associations between the selected markers and lung function. Our data show that different markers are associated with different lung function abnormalities, suggesting that these lung function abnormalities may be due to different underlying mechanisms. Interestingly, cytomegalovirus (CMV), which is a chronic viral infection common in HIV+ persons, has been associated with the three markers most strongly associated with one of the lung function abnormalities. These data lead to the following specific aims: Aims 1 and 2: To test the hypothesis that persistent abnormalities in selected markers of immune activation, inflammation, lung injury, and cellular aging measured in the blood are associated with subsequent changes (declines) in lung function and that the specific markers associated with each lung function abnormality will be different. The longitudinal study design will strengthen the causal inferences from our earlier work and will set the foundation for future trials of therapeutic interventions, including the potential for personalized medicine with potentially novel and/or different therapies for different biomarker and/or different lung function abnormalities. Aim 3. In a cross-sectional subset of HIV+ participants selected to undergo bronchoscopy and collect lung specimens, to test the hypothesis that abnormalities in the same markers but now measured in lung specimens are associated with abnormal lung function and test the hypothesis that asymptomatic CMV co-infection is also associated with lung function abnormalities and is mediated by these markers. This aim will determine whether CMV co-infection is involved in lung function abnormalities and potentially set the stage for trials of anti-CMV therapy in HIV+ COPD. To address these aims, we will conduct a longitudinal study of 400 HIV+ subjects (200 in the US and 200 in Uganda) and collect and bank blood specimens at the same time as lung function testing. We will also perform bronchoscopy in a subset of 80 subjects (40 in the US and 40 in Uganda) and collect and bank lung specimens and specimens to assess for CMV co-infection at the same time as lung function testing. The banked specimens will allow for efficient testing of new and novel markers in the future. Our long-term objective is to improve our mechanistic understanding of lung function abnormalities seen in persons with HIV that would lead to a future study that tests new treatments for this important and growing clinical problem.

抽象的 慢性阻塞性肺病 (COPD) 是一种与 HIV 相关的肺部疾病，也是导致慢性阻塞性肺病的主要原因 随着全球艾滋病毒+人群的老龄化，其发病率和死亡率及其临床意义日益增加。尽管 因此，我们对 HIV+ COPD 潜在机制的了解有限，但 HIV 相关性和 COPD- 假设了具体机制。加深理解对于开发新疗法至关重要 治疗或预防这个日益严重的问题。这项研究建立在一个新颖的、成熟的跨国公司（美国和乌干达）的基础上 HIV+ 人群。该研究测量了免疫激活、炎症、肺损伤、 以及血液和肺样本中的细胞老化。该研究还进行了肺功能测试 检查所选标记物与肺功能之间的关联。我们的数据显示不同的标记 与不同的肺功能异常相关，表明这些肺功能异常可能 是由于不同的底层机制造成的。有趣的是，巨细胞病毒（CMV）是一种慢性病毒 HIV+ 人群中常见的感染，与与以下因素最密切相关的三个标志物有关： 肺功能异常之一。这些数据可实现以下具体目标： 目标 1 和 2：测试 假设免疫激活、炎症、肺损伤等选定标志物持续异常 血液中测量的细胞衰老与随后肺功能的变化（下降）有关 与每种肺功能异常相关的特定标志物会有所不同。纵向研究 设计将加强我们早期工作的因果推论，并为未来的试验奠定基础 治疗干预措施，包括具有潜在新颖和/或不同的个性化医疗的潜力 针对不同生物标志物和/或不同肺功能异常的疗法。目标 3. 在横截面子集中 的 HIV+ 参与者被选择接受支气管镜检查并收集肺部标本，以检验以下假设： 现在在肺标本中测量的相同标记物的异常与肺异常相关 功能并检验无症状巨细胞病毒合并感染也与肺功能相关的假设 异常并由这些标记介导。该目标将确定是否涉及 CMV 合并感染 肺功能异常，并可能为 HIV+ COPD 的抗 CMV 治疗试验奠定基础。到 为了实现这些目标，我们将对 400 名 HIV+ 受试者（美国 200 名，乌干达 200 名）进行纵向研究 并在肺功能检测的同时采集并储存血液标本。我们还将表演 对 80 名受试者（美国 40 名，乌干达 40 名）进行支气管镜检查，并收集和储存肺部标本 以及在肺功能测试的同时评估 CMV 合并感染的样本。储存的标本 将允许在未来有效地测试新的和新颖的标记。我们的长期目标是提高我们的 对艾滋病毒感染者肺功能异常的机制理解将带来未来 研究测试针对这一重要且日益严重的临床问题的新疗法。

项目成果

Immune Response and Mortality Risk Relate to Distinct Lung Microbiomes in Patients with HIV and Pneumonia.

免疫反应和死亡风险与艾滋病毒和肺炎患者的不同肺部微生物组有关。

• 发表时间: 2017
• 影响因子: 24.7
• 作者: Shenoy, Meera K;Iwai, Shoko;Lin, Din L;Worodria, William;Ayakaka, Irene;Byanyima, Patrick;Kaswabuli, Sylvia;Fong, Serena;Stone, Stephen;Chang, Emily;Davis, J Lucian;Faruqi, Ali Ahmad;Segal, Mark R;Huang, Laurence;Lynch, Susan V
• 通讯作者: Lynch, Susan V

Stress and telomere shortening: Insights from cellular mechanisms.

压力和端粒缩短：细胞机制的见解。

• 发表时间: 2022
• 影响因子: 13.1
• 作者: Lin, Jue;Epel, Elissa
• 通讯作者: Epel, Elissa

Predictors and short-term outcomes of recurrent pulmonary tuberculosis, Uganda: a cohort study.

乌干达复发性肺结核的预测因素和短期结果：一项队列研究。

• 发表时间: 2017
• 作者: Kalema, Nelson;Lindan, Christina;Glidden, Dave;Yoo, Samuel D;Katamba, Achilles;Alfred, Andama;Katagira, Winceslaus;Byanyima, Patrick;Musisi, Emmanuel;Kaswabuli, Sylvia;Ingvar, Sanyu;Zawedde, Josephine;Yoon, Christina;Ayakaka, Irene;Davis, J
• 通讯作者: Davis, J

Sex modifies the risk of HIV-associated obstructive lung disease in Ugandans postpneumonia.

性别改变了肺炎后乌干达人患艾滋病毒相关阻塞性肺病的风险。

• 发表时间: 2023-09-01
• 作者: Abelman, Rebecca A;Fitzpatrick, Jessica;Zawedde, Josephine;Sanyu, Ingvar;Byanyima, Patrick;Kaswabuli, Sylvia;Musisi, Emmanuel;Hsieh, Jenny;Gardner, Kendall;Zhang, Michelle;Byanova, Katerina L;Sessolo, Abdul;Hunt, Peter W;Lalitha, Rejani;Davi
• 通讯作者: Davi

Response to: 'No long-term effect of past Pneumocystis jirovecii pneumonia on pulmonary function in people with HIV'.

回应：“过去的耶氏肺孢子虫肺炎对艾滋病毒感染者的肺功能没有长期影响”。

• 发表时间: 2023-11-15
• 作者: Byanova, Katerina L;Huang, Laurence
• 通讯作者: Huang, Laurence