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: 10669261
• 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/10669261
• 关键词: Address; Adult; Advisory Committees; Aftercare; Agonist; Airway Disease; Allergens; 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; Institution; Insulin Resistance; Internal Medicine; Intervention; Link; Measures; Mediating; Mediator; 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; Reporting; Research Design; Research Personnel; Research Support; Resources; Risk; Risk Reduction; 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; randomized, clinical trials; 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 尽管哮喘患者的代谢失调患病率很高，但精度机制 驾驶该人群中的气道炎症尚未确立。糖皮质激素是 治疗哮喘，但损害代谢控制，发病率增加并驱动医疗费用。 因此，紧急，未满足的需要了解代谢途径在哮喘和 靶向疗法的影响。该建议旨在通过检查针对目标的影响来满足需求 哮喘和代谢患者的胰高血糖素样肽-1受体（GLP-1R）代谢途径 失调。越来越多的证据支持GLP-1R激动剂（GLP-1RA）减少气道 炎。初步临床前数据还支持GLP-1RAS减少血小板激活和介体 释放和临床上，GLP-1RA会减少不良心血管事件。血小板是共享的来源 目前的哮喘治疗方法无法解决气道和代谢疾病的促疾病介质。 因此，该提案旨在检验以GLP-1RA增强GLP-1途径的假设 治疗会影响血小板注射介导的临床哮喘结局。长期目标是 扩大需要糖皮质激素治疗干预措施的患者的治疗选择。具体来说， 拟议的目标将1）评估血小板激活对哮喘患者哮喘恶化的影响 哮喘和2型糖尿病（T2DM）使用电子健康记录的生物库； 2）前瞻性 检查GLP-1RA计划对哮喘患者气道注射临床测量的影响 和T2DM接受常规门诊糖尿病护理； 3）确定基线血小板的影响 哮喘和肥胖症患者对GLP-1RA治疗的临床反应激活，利用数据 我们的合作者凯瑟琳·卡希尔（Katherine Cahill）博士是一项随机，安慰剂对照的临床试验。这些目标直接保持一致 随着国家心脏，肺和血液研究所的核心科学使命，以支持改进的研究 哮喘治疗方案，并另外解决了增加的患病率的健康后果 哮喘人群的T2DM和肥胖症。具体目标完成了强大的培训Agernda 候选人为独立做准备，并与糖尿病的严格，动手的课程保持一致 代谢，临床研究设计，生物统计分析和实用生物信息学方法 研究，在大众杨百翰卫生系统的特殊科学环境中 哈佛医学院。 Foer博士的主要导师Joshua Boyce博士和同事Elizabeth Karlson博士， 为候选人提供协调的内容和方法论专家，以促进她的专业人士 发展和研究目标。一个科学咨询委员会，由肺科专家组成， 内分泌学和一般内科医学进一步致力于时间，资源和专业知识 填补该提议的承诺，以有意义地改善哮喘患者的护理和健康。