GEMSSTAR PERSPIRE-COPD

GEMSSTAR 出汗-慢性阻塞性肺病

• 批准号: 10724784
• 负责人: Christopher Mosher
• 金额: $ 16.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724784
• 关键词: Acceleration; Active Learning; Acute; Address; Adult; American; Award; Biological; Biological Markers; Biology of Aging; CD28 gene; CDKN2A gene; Capsicum; Caring; Cells; Characteristics; Chronic Obstructive Pulmonary Disease; Clinical Trials; Collaborations; Communities; Core Facility; Data; Development; Educational Intervention; Elderly; Enrollment; Event; Fostering; Frequencies; Funding; Future; Geriatrics; Goals; Hospitalization; Immunity; Immunology; Impairment; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Manuscripts; Measurement; Measures; Methodology; Modeling; Molecular; Patients; Pharmacological Treatment; Phenotype; Physical Performance; Physicians; Plasma; Play; Preparation; Prevention; Property; Public Health; Publishing; Pulmonology; Recovery; Research; Respiratory Tract Infections; Role; Scientist; Standardization; Structure; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Viral Respiratory Tract Infection; Vulnerable Populations; age related; biobank; career; career development; cytokine; design; disorder prevention; disorder risk; drug development; effective therapy; exercise intervention; exercise training; experience; health related quality of life; human old age (65+); immune system function; immunosenescence; improved; ineffective therapies; older patient; pharmacologic; phenotypic biomarker; physical conditioning; prevent; programmed cell death protein 1; programs; promote resilience; pulmonary rehabilitation; senescence; skill acquisition; symposium; translational scientist

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.

标题：肺部康复作为一种鼻溶液干预措施，以减少COPD的恶化 （Perspire-COPD） 项目摘要 慢性阻塞性肺疾病（AECOPD）的急性加重负责 美国年龄较大的成年人每年25万个住院（年龄≥65岁）。当前疗法无效 防止AECOPD导致迫切需要开发更有效的治疗方法。主要障碍 进步是确定可修改的生物学靶标。在目前可用的治疗中，肺部 康复（PR）在防止老年人的AECOPD方面安全有效。但是，生物学 尚不清楚负责预防AECOPD的机制。为了解决知识的差距， 我们将利用PR作为模型来识别可修改的生物学靶标，以防止AECOPD。我们的发现将允许 进一步的PR优化，并为未来的治疗药物开发提供生物学靶标。 宿主的免疫力可能在AECOPD预防中起重要作用，因为大多数事件是引起的 通过呼吸道病毒感染。考虑到这一点，我建议与年龄相关的免疫系统功能下降 （即免疫衰老）使患者容易受到更高的AECOPD风险。更大的免疫衰老导致 更多的AECOPD事件。免疫衰老的特征是高水平的感官T细胞和感应 相关的秘密表型（SASP）。消除感觉细胞（即鼻溶液）的疗法可以 有可能降低AECOPD风险。运动干预措施已显示以消除感官T细胞和 增加T细胞增殖。考虑到PR是一种运动训练干预措施。我假设该公关 将感觉T细胞的相对频率降低到幼稚的T细胞和SASP水平。这些变化将会 提高对呼吸道感染的韧性，降低AECOPD风险，并加速从AECOPD中恢复。在 为将来调查AECOPD风险的准备工作，我们将检验以下假设：PR与 与幼稚的T细胞和SASP水平相对频率的相对频率降低，并确定 这些变化随身体表现和HRQOL的改善而变化。开始解决这一行 调查，我已经开发了一个PR生物验证，该PR生物座位包含以标准化间隔收集的生物测量 以及物理性能和HRQOL的PR前/PR测量。 这些目标的完成将支持我的专业发展，以实现转化的职业 科学家专注于COPD老年人的衰老生物学和临床试验。宝石将加深 我对SASP生物标志物，T细胞免疫学，免疫衰老和受试者内方法的了解 并促进老年研究社区中的合作。该项目将导致3个发布 手稿，在国家会议上进行2次演讲，以及随后的K76 Paul B.的初步数据。 比森职业发展奖。 Gemsstar Award总之将对我的 作为独立的物理科学家和老年肺病学领导者的发展。