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

GLP-1 受体激动剂对哮喘气道炎症和血小板活化的影响

• 批准号: 10523701
• 负责人: Dinah Foer
• 金额: $ 19.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523701
• 关键词: Accounting; Address; Adult; Advisory Committees; Aftercare; Agonist; Airway Disease; Asthma; Attenuated; Automobile Driving; Bioinformatics; Biological Markers; Biometry; Blood Platelets; Body mass index; Cardiovascular system; Caring; Chronic Disease; Clinical; Clinical Research; Complement; Data; Deterioration; Development; Diabetes Mellitus; Disease Management; Drug usage; Electronic Health Record; Endocrinology; Endothelial Cells; Environment; Epithelial Cells; Event; Exhalation; FDA approved; Funding; Future; GLP-I receptor; Glucocorticoids; Goals; Health; Health Care Costs; Health system; High Prevalence; Homeostasis; Hyperglycemia; Inflammation; Inflammation Mediators; Inflammatory; Insulin Resistance; Internal Medicine; Intervention; Link; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Methodology; Methods; Mission; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Outpatients; Pathogenesis; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Placebos; Plasma; Platelet Activation; Platelet aggregation; Population; Positioning Attribute; Prevalence; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Pulmonology; Randomized Clinical Trials; Reporting; Research Design; Research Personnel; Research Support; Resources; Risk; Role; Sampling; Serum; Severities; Source; Symptoms; Testing; Therapeutic; Thinness; Time; Training; Viral; Weight Gain; airway hyperresponsiveness; airway inflammation; asthma exacerbation; biobank; cohort; comorbidity; diabetes management; diabetes mellitus therapy; glucagon-like peptide 1; glycemic control; health care service utilization; improved; in vivo; incretin hormone; medical schools; methacholine; mortality; mouse model; obese patients; obesity management; obesity-associated asthma; pleiotropism; pre-clinical; primary outcome; prospective; randomized placebo-controlled clinical trial; recruit; research and development; response; routine care; study population; targeted agent; targeted treatment

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.

项目概要/摘要 尽管哮喘患者代谢失调的患病率很高，但精确的机制 在这一人群中导致气道炎症的原因尚不明确。糖皮质激素是主要药物 治疗哮喘，但会损害代谢控制，增加发病率并增加医疗费用。 因此，迫切需要了解代谢途径在哮喘中的作用以及哮喘的发病机制。 靶向治疗的效果。该提案旨在通过研究针对以下目标的影响来满足这一需求： 哮喘患者胰高血糖素样肽-1受体（GLP-1R）代谢途径及其代谢 失调。越来越多的证据支持 GLP-1R 激动剂 (GLP-1RA) 药物可缩小气道 炎。初步临床前数据也支持 GLP-1RA 减少血小板活化和介质 GLP-1RA 的释放和临床上可减少不良心血管事件。血小板是共享的来源 目前的哮喘治疗尚未解决气道和代谢疾病中的促炎介质。 因此，本提案旨在检验用 GLP-1RA 增强 GLP-1 通路的假设 治疗影响由血小板炎症介导的临床哮喘结果。长期目标是 为需要糖皮质激素节约干预的患者扩大治疗选择。具体来说， 拟议的目标将 1) 评估血小板活化对患有以下疾病的患者哮喘加重的影响 使用与电子健康记录相关的生物库来分析哮喘和 2 型糖尿病 (T2DM)； 2）前瞻性地 检查 GLP-1RA 启动对哮喘患者气道炎症临床指标的影响 接受常规门诊糖尿病护理的 T2DM； 3) 确定基线血小板的影响 利用以下数据激活哮喘和肥胖患者对 GLP-1RA 治疗的临床反应 我们的合作者 Katherine Cahill 博士进行的一项随机、安慰剂对照临床试验。这些目标直接一致 国家心肺血液研究所的核心科学使命是支持改善疾病的研究 哮喘治疗方案，并另外解决哮喘患病率不断上升对健康造成的后果 T2DM 和哮喘人群的肥胖。这些具体目标补充了强有力的培训议程 候选人为独立做好准备，并与糖尿病和糖尿病领域严格的实践课程保持一致 代谢、临床研究设计、生物统计分析和临床实用生物信息学方法 在麻省总医院布里格姆卫生系统卓越的科学环境中进行研究， 哈佛医学院。 Foer 博士的主要导师 Joshua Boyce 博士和共同导师 Elizabeth Karlson 博士， 为候选人提供统一的内容和方法专业知识，以促进其专业发展 发展和研究目标。由肺病学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时间、资源和专业知识 履行该提案的承诺，切实改善哮喘患者的护理和健康。