GEMSSTAR PERSPIRE-COPD

标题：肺康复作为减少COPD病情恶化的降解性干预措施 (出汗-慢性阻塞性肺病) 项目摘要 慢性阻塞性肺疾病急性加重(AECOPD)导致 美国老年人(≥65岁)每年住院250,000次。目前的治疗方法在以下方面无效 预防AECOPD导致开发更有效的治疗方法的迫切和未得到满足的需求。一大障碍 要取得进展，就是确定一个可修改的生物目标。在目前可用的治疗方法中，肺 康复(PR)在预防老年人AECOPD方面是安全有效的。然而，生物学上的 对AECOPD预防负责的机制尚不清楚。为了解决这一知识差距， 我们将利用PR作为一个模型来确定可修改的生物靶点，以预防AECOPD。我们的发现将允许 进一步优化PR，为未来的治疗药物开发提供生物靶点。 宿主免疫可能在AECOPD预防中发挥重要作用，因为大多数事件都是由 由呼吸道病毒感染引起。考虑到这一点，我认为与年龄相关的免疫系统功能下降 (即免疫衰老)使患者易患更高的AECOPD风险。更强的免疫衰老导致 更多的AECOPD活动。免疫衰老的特征是高水平的衰老T细胞和衰老 相关分泌表型(SASP)。消除衰老细胞的疗法(即抗衰老药物)可能 潜在降低AECOPD风险。运动干预已被证明可以清除衰老的T细胞和 促进幼稚T细胞的增殖。认为PR是一种运动训练干预。我假设公关 将衰老T细胞的相对频率降低到幼稚T细胞和SASP水平。这些变化将 提高对呼吸道感染的复原力，降低AECOPD风险，并加快从AECOPD恢复。在……里面 为未来对AECOPD风险的调查做准备，我们将检验PR与 衰老与幼稚T细胞的相对频率和SASP水平的降低以及确定 这些变化伴随着体能和HRQOL的改善。要开始解决这一行 调查，我已经开发了一个PR生物储存库，其中包含以标准化间隔收集的生物检疫 以及PR前后的体能表现和HRQOL测量。 完成这些目标将支持我的职业发展，成为一名翻译 科学家，专注于老年COPD患者的衰老生物学和临床试验。GEMSSTAR将加深 我对SASP生物标记物、T细胞免疫学、免疫衰老和受试者内方法学的了解 并促进老年医学研究社区内的合作。该项目将导致3个出版 手稿，在国家会议上的两次演讲，以及随后K76保罗·B的初步数据。 比森职业发展奖。总之，GEMSSTAR奖将对我的 发展成为一名独立的内科科学家和未来老年肺病学的领导者。

TITLE: Pulmonary Rehabilitation as a Senolytic Intervention to Reduce Exacerbations in COPD (PERSPIRE-COPD) PROJECT ABSTRACT Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are responsible for over 250,000 hospitalizations per year in older American adults (age ≥ 65). Current therapies are ineffective at preventing AECOPD resulting in an urgent and unmet need to develop more effective treatments. A major barrier to progress is identification of a modifiable biologic target. Among currently available treatments, pulmonary rehabilitation (PR) is safe and effective at preventing AECOPD in older adults. However, the biological mechanisms responsible for AECOPD prevention are not well understood. To address this gap in knowledge, we will leverage PR as a model to identify modifiable biologic targets to prevent AECOPD. Our findings will allow further PR optimization and provide biologic targets for future therapeutic drug development. Host immunity likely plays an important role in AECOPD prevention as a majority of events are caused by respiratory viral infections. Considering this, I propose that age-related decline in immune system function (i.e. immunosenescence) predisposes patients to higher AECOPD risk. Greater immunosenescence leads to more AECOPD events. Immunosenescence is characterized by high levels of senescent T-cells and senescence associated secretory phenotype (SASP). Therapies that eliminate senescent cells (i.e. senolytics) could potentially lower AECOPD risk. Exercise interventions have been shown to remove senescent T-cells and increase naïve T-cell proliferation. Considering PR is an exercise training intervention. I hypothesize that PR reduces the relative frequency of senescent T-cells to naïve T-cells and SASP levels. These changes will increase resilience to respiratory infections, lower AECOPD risk, and accelerate recovery from AECOPD. In preparation for future investigations into AECOPD risk, we will test the hypothesis that PR is associated with a decrease in relative frequency of senescent to naïve T-cells and SASP levels and determine the correlation of these changes with an improvement in physical performance and HRQoL. To begin to address this line of investigation, I’ve developed a PR biorepository that contains biospecimens collected at standardized intervals and pre/post-PR measurements of physical performance and HRQoL. Completion of these aims will support my professional development towards a career as a translational scientist with a focus in aging biology and clinical trials in older adults with COPD. The GEMSSTAR will deepen my knowledge of SASP biomarkers, T-cell immunology, immunosenescence, and within-subjects methodology and foster collaborations within the geriatrics research community. The project will result in 3 published manuscripts, 2 presentations at national conferences, and preliminary data towards a subsequent K76 Paul B. Beeson Career Development Award. Altogether, the GEMSSTAR award will play a critical role towards my development as an independent physician scientist and future leader in geriatric pulmonology.