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

摘要（多样性补充） 慢性阻塞性肺疾病（COPD）是慢性阻塞性肺疾病患者发病和死亡的主要原因。 随着HIV+人群年龄的增长，其临床意义也在增加。治疗或预防这种疾病的新疗法 日益严重的问题将需要改进的机械见解。然而，我们目前对 HIV+ COPD的发病机制是有限的，但HIV相关和COPD特异性机制都是 假设的“我老了”研究旨在通过一种新颖的、建立在 多国（美国和乌干达）艾滋病毒阳性者队列。这项研究是衡量艾滋病毒相关和COPD特异性 血液中的免疫激活、炎症、肺损伤和细胞老化的标志物，以及执行肺功能 试验.它正在检查所选标记物与肺功能（肺量测定和弥散）之间的关系 一氧化碳容量，DLco）。我们的中心假设是：（1）不同的致病机制 肺功能异常和DLco异常的基础;（2）不同的致病机制 COPD/肺气肿（即，异常肺活量测定和异常DLco）和DLco的孤立减少（即， 肺功能测定正常的异常DLco），下文称为iso↓DLco。为了验证这一假设，我们提出 三个目标，其中前两个在这里详细介绍，是本多样性补充提案的一部分：目标1： 为了检验免疫激活、炎症、肺损伤等标志物的持续异常， 外周血中测量的细胞老化与随后的FEV 1/FVC变化（下降）相关 FEV1。目的2A和2B：检验以下假设：测量的相同标志物中的持续异常 与DLco随后的变化（下降）相关， COPD/肺气肿患者弥散异常与iso↓DLco相关的标志物不同。 这个多样性补充我老DA研究将支持一个有价值的学士后学者 来自一个贫困的背景谁寻求未来的职业生涯作为一个物理学家，科学家，并将为他提供 基本的研究培训，指导和实践经验，以支持他申请医学院。 多样性补充目标1：检验血浆IL-6和hsCRP（非特异性）持续升高的假设。 先前与异常肺量测定相关的炎症的特异性标志物）与 随后的肺功能测定下降：FEV 1/FVC和FEV 1。目标2A：检验持续性的假设 血浆肺和活化调节趋化因子（PARC/CCL-18）和俱乐部细胞分泌 蛋白-16（CC-16）（以前与异常DLco相关）与随后的 DLco。目的2B：检验血浆可溶性肿瘤坏死因子受体持续升高的假设， 2（sTNFR-II）和干扰素γ诱导蛋白-10（IP-10）（既往与异常iso↓DLco相关） 与iso↓DLco的后续变化（下降）相关。这些目标的成功将改善 我们目前对艾滋病毒+慢性阻塞性肺病的了解，并使这位杰出的学士后学者受益。

ABSTRACT (Diversity Supplement) Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in persons with HIV, and its clinical significance is increasing as the HIV+ population ages. New therapies to treat or prevent this growing problem will require improved mechanistic insights. However, our current understanding of the pathogenesis underlying HIV+ COPD is limited, but both HIV-related and COPD-specific mechanisms are hypothesized. The I AM OLD-DA Study seeks to improve our understanding using a novel, established multinational (US and Uganda) cohort of HIV+ persons. The study is measuring HIV-related and COPD-specific markers of immune activation, inflammation, lung injury, and cellular aging in blood and performing lung function testing. It is examining the associations between the selected markers and lung function (spirometry and diffusion capacity for carbon monoxide, DLco). Our central hypothesis is that: (1) different pathogenic mechanisms underlie abnormal spirometry and abnormal DLco and (2) different pathogenic mechanisms underlie COPD/emphysema (i.e., abnormal spirometry and abnormal DLco) and isolated reductions in DLco (i.e., abnormal DLco with normal spirometry), referred to as iso↓DLco hereafter. To test this hypothesis, we proposed three Aims, the first two of which are detailed here and are part of this Diversity Supplement proposal: Aim 1: To test the hypothesis that persistent abnormalities in markers of immune activation, inflammation, lung injury, and cellular aging measured in peripheral blood are associated with subsequent changes (declines) in FEV1/FVC and FEV1. Aims 2A and 2B: To test the hypothesis that persistent abnormalities in the same markers measured in peripheral blood are associated with subsequent changes (declines) in DLco and that the markers associated with diffusion abnormalities in COPD/emphysema will be different from the markers associated with iso↓DLco. This Diversity Supplement to the I AM OLD-DA Study will support a meritorious post-baccalaureate scholar from an under-privileged background who seeks a future career as a physician-scientist and will provide him with essential research training, mentoring, and hands-on experience in support of his application to medical school. Diversity Supplement Aim 1: To test the hypothesis that persistent elevations in plasma IL-6 and hsCRP (non- specific markers of inflammation previously associated with abnormal spirometry) are associated with subsequent declines in spirometry: FEV1/FVC and FEV1. Aim 2A: To test the hypothesis that persistent elevations in plasma pulmonary and activation-regulated chemokine (PARC/CCL-18) and club cell secretory protein-16 (CC-16) (previously associated with abnormal DLco) are associated with subsequent declines in DLco. Aim 2B: To test the hypothesis that persistent elevations in plasma soluble tumor necrosis factor receptor 2 (sTNFR-II) and interferon gamma-inducible protein-10 (IP-10) (previously associated with abnormal iso↓DLco) are associated with subsequent changes (declines) in iso↓DLco. The success of these aims will both improve our current understanding of HIV+ COPD and benefit this meritorious post-baccalaureate scholar.