Effects of GLP-1 Receptor Agonists on Airway Inflammation and Platelet Activation in Asthma

项目总结/摘要 尽管哮喘患者中代谢失调的患病率很高，但确切的机制 在这一人群中，驱动气道炎症的机制尚未得到充分证实。糖皮质激素是 治疗哮喘，但损害代谢控制，增加发病率和推动医疗保健成本。 因此，迫切需要了解代谢途径在哮喘中的作用， 靶向治疗的效果。这项建议旨在通过审查将目标对准 哮喘患者胰高血糖素样肽-1受体（GLP-1 R）代谢途径及代谢 失调越来越多的证据支持GLP-1 R激动剂（GLP-1 RA）药物降低气道 炎症初步临床前数据也支持GLP-1 RA可降低血小板活化和介导 在临床上，GLP-1 RA可减少不良心血管事件。血小板是一个共同的来源， 气道和代谢性疾病中的促炎介质，目前的哮喘治疗没有解决。 因此，本提案旨在检验GLP-1 RA增强GLP-1途径的假设 治疗通过血小板炎症介导影响临床哮喘结果。长期目标是 为需要糖皮质激素保留干预的患者扩大治疗选择。具体而言是 提出的目标是：1）评估血小板活化对哮喘急性发作患者的影响， 哮喘和2型糖尿病（T2 DM），使用电子健康记录链接的生物库; 2）前瞻性 检查GLP-1 RA启动对哮喘患者气道炎症临床指标的影响 和接受常规门诊糖尿病护理的T2 DM;和3）确定基线血小板 哮喘和肥胖患者对GLP-1 RA治疗临床应答的激活，利用来自 我们的合作者凯瑟琳卡希尔博士进行的一项随机、安慰剂对照临床试验。这些目标直接与 与国家心脏，肺和血液研究所的核心科学使命，以支持研究，改善 哮喘治疗方案，并另外解决日益普遍的健康后果， 哮喘人群的T2 DM和肥胖。这些具体目标补充了一个强有力的培训议程， 候选人为独立做准备，并与糖尿病严格的实践课程保持一致， 代谢，临床研究设计，生物统计学分析和临床实用的生物信息学方法 研究，在特殊的科学环境中，在马萨诸塞州总布里格姆卫生系统和 哈佛医学院。福尔博士的主要导师，约书亚博伊斯博士和共同导师，伊丽莎白卡尔森博士， 为候选人提供统一的内容和方法专门知识，以促进她的专业 发展和研究目标。由肺病专家组成的科学咨询委员会， 内分泌科和普通内科进一步投入了时间、资源和专业知识， 履行该提案的承诺，有意义地改善哮喘患者的护理和健康。

PROJECT SUMMARY/ABSTRACT Despite the high prevalence of metabolic dysregulation among patients with asthma, precise mechanisms driving airway inflammation in this population are not well-established. Glucocorticoids are a mainstay of treatment for asthma but damage metabolic control, increasing morbidity, and driving healthcare costs. Therefore, there is an urgent, unmet need to understand the role of metabolic pathways in asthma and the effect of targeted therapies. This proposal aims to meet that need by examining the effects of targeting the glucagon-like peptide-1 receptor (GLP-1R) metabolic pathway in patients with asthma and metabolic dysregulation. Increasing evidence supports that GLP-1R agonist (GLP-1RA) drugs reduce airway inflammation. Preliminary preclinical data also support that GLP-1RAs reduce platelet activation and mediator release, and clinically, GLP-1RAs decrease adverse cardiovascular events. Platelets are a shared source of pro-inflammatory mediators in airway and metabolic disease not addressed by current asthma therapies. Therefore, this proposal aims to test the hypothesis that augmenting the GLP-1 pathway with GLP-1RA therapy impacts clinical asthma outcomes, mediated by platelet inflammation. The long-term objective is to expand therapeutic options for patients in need of glucocorticoid-sparing interventions. Specifically, the proposed aims will 1) evaluate the impact of platelet activation on asthma exacerbations in patients with asthma and type 2 diabetes (T2DM) using an electronic health record-linked Biobank; 2) prospectively examine the effect of GLP-1RA initiation on clinical measures of airway inflammation in patients with asthma and T2DM receiving routine outpatient diabetes care; and 3) determine the impact of baseline platelet activation on clinical response to GLP-1RA treatment in patients with asthma and obesity, leveraging data from a randomized, placebo-controlled clinical trial by our collaborator Dr. Katherine Cahill. These aims directly align with the National Heart, Lung, and Blood Institute’s core scientific mission to support research that improves asthma treatment options, and additionally address the health consequences of the increasing prevalence of T2DM and obesity for the asthma population. The specific aims complement a robust training agenda for the candidate to prepare for independence and are aligned with rigorous, hands-on coursework in diabetes and metabolism, clinical study design, biostatistical analysis, and practical bioinformatics methods for clinical research, within the exceptional scientific environment at the Mass General Brigham health system and Harvard Medical School. Dr. Foer’s primary mentor, Dr. Joshua Boyce and co-mentor, Dr. Elizabeth Karlson, provide harmonized content and methodology expertise for the candidate to facilitate her professional development and research goals. A scientific advisory committee composed of experts in Pulmonology, Endocrinology, and General Internal Medicine have further committed the time, resources, and expertise to fulfill the promise of this proposal to meaningfully improve the care and health of patients with asthma.