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.

PROJECT NARRATIVE Metabolic dysregulation is a common and challenging comorbidity in patients with asthma that increases morbidity, mortality and healthcare costs. We will study the effects of targeting the glucagon-like peptide-1 receptor (GLP-1R) pathway on clinical measures of airway inflammation in adults with asthma, using GLP-1R agonist drugs which are already FDA approved for treatment of type 2 diabetes and obesity. Characterizing the effect of GLP-1R agonists on asthma clinical outcomes and mediators of airway inflammation could inform treatment benefits and patient selection, leading to personalized, glucocorticoid-sparing interventions that reduce risk and improve chronic disease management in asthma.