Project Summary Multiple preclinical and clinical studies show that glucagon-like peptide-1 receptor (GLP-1R) agonists, FDA approved agents used in type 2 diabetes, obesity, and cardiovascular risk reduction, are a promising novel treatment strategy for asthma. However, the key cellular targets and mechanisms by which GLP-1R agonists reduce airway inflammation in asthma remain poorly understood. The rationale for the proposed research is that a better understanding of the cellular targets and anti-inflammatory mechanisms of GLP-1 signaling is required in order to maximize the clinical use of GLP-1R agonists for the treatment of both lean and obese patients with asthma. The overall objective in this proposal is to identify the direct immunologic mechanisms by which GLP-1 signaling reduces inflammation to inform the clinical repurposing of GLP-1R agonists in asthma. The central hypothesis, based on preliminary data generated in the investigators’ laboratories, is that GLP-1R agonists directly attenuate both type (T)2 and non-T2 cells and mediators in asthma. Guided by robust preliminary data which supports that GLP-1R signaling regulates the function of specific human immune cells, we will test our central hypothesis in two distinct, but highly integrated specific aims. We will determine the anti- inflammatory role of GLP-1 signaling in 1) platelet-derived T2 and non-T2 inflammation and 2) CD4+ T cell function in asthma. In aim 1, we will evaluate platelets from lean and obese asthma patients to determine the role of GLP-1 signaling on platelet inflammatory mediator release (aim 1a). We will assess platelet aggregation as a biomarker of the inflammatory and clinical response to GLP-1R agonist therapy (aim 1b), and the effect of GLP-1R agonist therapy on platelet activation and platelet-leukocyte formation in patients with asthma (aim 1c). In aim 2, we will evaluate CD4+ T cells and platelet-adherent CD4+ T cells from lean and obese asthma patients to determine the role of GLP-1 signaling on CD4+ T cell subset differentiation (aim 2a). We will assess the effect of GLP-1R agonist therapy on CD4+ T cell activation in patients with asthma (aim 2b). This proposal capitalizes on sample collection and mechanistic and clinical data from the investigator’s ongoing randomized controlled trial of a GLP-1R agonist in asthma with comorbid obesity. This fully human approach is innovative because it defines how GLP-1R agonists regulate multiple key immune cell populations, independent of GLP- 1R agonist effects on comorbid metabolic disease. This proposal is significant because it defines a precision medicine approach for repurposing GLP-1R agonists in both lean and obese patients with asthma. This study will inform the use of GLP-1R agonists in asthma and other inflammatory diseases in the absence of metabolic comorbidity.