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GLP-1R agonist immune targets in lean and obesity-associated asthma

Award Number: R01AI182159
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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GLP-1R agonist immune targets in lean and obesity-associated asthma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $745,797 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	2	6/20/2025	NON-COMPETING CONTINUATION	$745,797
														Subtotal = $745,797

Issue Date FY: 2024 ( Subtotal = $746,134 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	8/16/2024	NEW	$671,520
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Allergy and Infectious Diseases Research	001	1	9/17/2024	NEW	$74,614
														Subtotal = $746,134

Grand Total All Awards = $1,491,931

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GLP-1R agonist immune targets in lean and obesity-associated asthma

Award Number: R01AI182159

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/16/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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