Air Pollution's Impact on Lung Aging in HIV

项目摘要 今天，艾滋病毒感染者（PLWH）面临着慢性呼吸道疾病的过度负担， 加速肺老化尽管研究的进展增加了我们对肺部疾病的理解 在PLWH中，我们对影响高危人群肺部健康的因素的认识存在重大差距。 人口全球环境空气污染仍然是一个重要的，但可以改变的，慢性 呼吸道疾病和疾病发展。虽然转化研究表明， 对香烟烟雾的敏感性，这是否适用于长期暴露于环境空气污染，还没有 研究了到目前为止，长期暴露于空气污染对艾滋病毒肺老化的影响仍然未知。的 HIV感染在肺部疾病病因学中的研究（SHIELD），一项2600例患者的前瞻性队列研究， 或艾滋病毒的风险在巴尔的摩，MD，提供了一个理想的平台，有效地回答有关的影响问题， 环境对肺老化的影响。基于现有的盾牌队列，我们的目标是确定， 长期的环境空气污染是加速高危人群肺老化的驱动因素，如果 PLWH更容易受到污染物暴露对呼吸系统健康的影响。 这项拟议中的研究将独特地描述环境、艾滋病毒和肺老化之间的相互作用。 我们将通过增强的精确度和深度CT来增加长期环境空气污染的精细测量 表型分析，以捕捉早期肺部疾病，以及生物老化和易感性的分子标志物， 暴露，同时利用来自明确定义的PLWH队列的纵向肺功能数据。我们提出 三个目的是研究长期暴露对多维（生理，放射学， PLWH中的肺老化。(Aim 1）确定长期环境污染物与 暴露和生理性肺老化（肺功能下降的轨迹）和健康相关的生活质量， PLWH和类似的未感染HIV的参与者;（目标2）定义长期污染物暴露的影响 PLWH中影像学肺老化（小气道疾病、空气潴留、肺气肿）的CT测量; (Aim 3）确定长期污染物暴露与加速“生物”老化之间的关系， 通过表观遗传时钟测量，表观遗传时钟是生物反应和对污染物敏感性的分子标记 exposure.在所有目标中，我们将研究艾滋病毒和艾滋病毒控制标志物如何增加对空气污染的敏感性。 这项建议将提供指导培训，以执行环境群组研究， 艾滋病毒肺部疾病研究的复杂性，先进的生物统计学方法，肺部新的CT分析技术 表型，以及表观遗传标记的应用，以描述生物反应和易感性， 暴露。职业发展计划包括专家指导、正式课程和动手实践 经验，以促进博士拉贾在实现他的职业目标，成为一个独立的医生科学家， 在环境健康差异，艾滋病毒和肺部健康研究的交叉专业知识。

PROJECT SUMMARY Today, persons living with HIV (PLWH) face a disproportionate burden of chronic respiratory disease and accelerated lung aging. Despite advances in research that have increased our understanding of lung disease among PLWH, there are significant gaps in our knowledge of factors that impact lung health in this at-risk population. Worldwide ambient air pollution remains a significant, but modifiable, contributor to chronic respiratory morbidity and disease development. While translational studies suggest that HIV increases susceptibility to cigarette smoke, whether this applies to long-term ambient air pollution exposure has not been studied. To date, the impact of long-term air pollution exposure on lung aging in HIV remains unknown. The Study of HIV Infection in the Etiology of Lung Disease (SHIELD), a prospective cohort of 2600 individuals with or at-risk for HIV in Baltimore, MD, provides an ideal platform to efficiently answer questions about the impact of the environment on lung aging for PLWH. Building on the existing SHIELD cohort, we aim to determine if long-term ambient air pollution is a driver of accelerated lung aging in a high-risk population, and if PLWH are more susceptible to the respiratory health effects of pollutant exposure. The proposed research will uniquely characterize the interaction between the environment, HIV, and lung aging. We will add refined measures of long-term ambient air pollution with enhanced precision, in-depth CT phenotyping to capture early lung disease, and molecular markers of biologic aging and susceptibility to exposures, while leveraging longitudinal lung function data from a well-defined cohort of PLWH. We propose three aims to study the impact of long-term exposures on multidimensional (physiologic, radiographic, and biologic) lung aging among PLWH. (Aim 1) To determine the association between long-term ambient pollutant exposure and physiologic lung aging (trajectory of lung function decline) and health related quality of life for PLWH and comparable HIV-uninfected participants; (Aim 2) To define the impact of long-term pollutant exposure on CT measures of radiographic lung aging (small airways disease, air trapping, emphysema) among PLWH; (Aim 3) To determine the association between long-term pollutant exposure and accelerated “biologic” aging, measured via the epigenetic clock, a molecular marker of biologic responses and susceptibility to pollutant exposure. In all aims we will examine how HIV and markers of HIV control increase susceptibility to air pollution. This proposal will provide mentored training in the implementation of an environmental cohort study, the complexities of HIV-lung disease research, advanced biostatical methods, novel CT analysis techniques for lung phenotyping, and the application of epigenetic markers to describe biologic responses and susceptibility to exposures. The career development plan includes expert mentorship, formal coursework, and hands-on experience to facilitate Dr. Raju in achieving his career goal of becoming an independent physician scientist with expertise at the intersection of environmental health disparities, HIV, and lung health research.