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.

项目摘要/摘要 尽管哮喘患者中代谢紊乱的发生率很高，但确切的机制 在这一人群中，推动呼吸道炎症的机制还没有得到很好的证实。糖皮质激素是一种主要的 治疗哮喘，但损害新陈代谢控制，增加发病率，并推高医疗成本。 因此，有一个迫切的，尚未得到满足的需要，以了解代谢途径在哮喘和 靶向治疗的效果。这项提案旨在通过审查针对 高血糖素样多肽-1受体(GLP-1R)代谢途径在哮喘及代谢中的作用 监管失调。越来越多的证据支持GLP-1R激动剂(GLP-1RA)药物减少呼吸道 发炎。初步的临床前数据也支持GLP-1RAs减少血小板活化和介质 释放，临床上，GLP-1RAs可减少不良心血管事件。血小板是一个共同的来源 呼吸道和代谢性疾病中的促炎介质没有被目前的哮喘治疗方法解决。 因此，这一建议旨在检验用GLP-1RA增强GLP-1途径的假设 治疗通过血小板炎症影响哮喘的临床转归。长期目标是 为需要非糖皮质激素干预的患者扩大治疗选择。具体地说， 建议的AIMS将1)评估血小板激活对以下患者哮喘加重的影响 哮喘和2型糖尿病(T2 DM)：使用与电子健康记录关联的生物库；2)前瞻性 检测GLP-1RA启动对哮喘患者呼吸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；以及3)确定基线血小板的影响 哮喘和肥胖症患者对GLP-1RA治疗的临床反应的激活，利用来自 我们的合作者凯瑟琳·卡希尔博士进行了一项随机、安慰剂对照的临床试验。这些目标直接一致 与国家心肺血液研究所的核心科学使命一起支持改善 哮喘治疗选择，并另外解决日益流行的哮喘的健康后果 哮喘人群中2型糖尿病与肥胖的关系。这些具体目标补充了一项强有力的培训议程 准备独立的候选人，并与严格的、动手操作的糖尿病课程和 代谢、临床研究设计、生物统计分析和临床实用的生物信息学方法 在马萨诸塞州布里格姆卫生系统的特殊科学环境下进行的研究 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， 为应聘者提供协调的内容和方法专业知识，以促进她的专业 开发和研究目标。由肺病学专家组成的科学咨询委员会， 内分泌学和普通内科进一步投入了时间、资源和专业知识 履行这项提案的承诺，切实改善哮喘患者的护理和健康。