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Attenuation of sepsis-induced microvascular permeability and inflammation with the GLP-1R agonist liraglutide.

Award Number: F31HL178162
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Attenuation of sepsis-induced microvascular permeability and inflammation with the GLP-1R agonist liraglutide. - Project Abstract Sepsis is a critical problem around the world causing 20% of all global deaths. The lack of effective therapeutics leaves critically ill patients with systemic organ dysfunction often caused by damage to the vascular endothelium. The damage induces micro-vessel dysfunction and increased permeability. Increased permeability can be attributed to tight junction and adherens junction disruption within endothelial cells. All blood vessels are lined with a single cell layer of endothelial cells that regulate exchanges between the bloodstream and the surrounding tissues and modulate inflammation. During sepsis, endothelial cells secrete circulating inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) which cause upregulation of cell adhesion molecules that facilitate leukocyte trafficking and also MCP-1 also disrupts tight junctions in endothelial cells. Given the widespread vascular inflammation and breakdown of endothelial tight junctions in sepsis, therapeutic approaches to maintain and restore endothelial tight junctions is a compelling treatment strategy. GLP-1R agonists have unexpected anti-inflammatory and permeability attenuation effects. Preliminary in vitro studies suggest that the protective effects of the GLP-1R agonist, liraglutide, in sepsis are mediated through microvascular endothelium. Pre-treatment of primary human lung microvascular endothelial cells with liraglutide improved lipopolysaccharide-induced barrier dysfunction indicating important effects of liraglutide in protecting the endothelial barrier. In Aim 1, I will define the ability of liraglutide to attenuate microvascular permeability in vitro and in a clinically relevant murine model of polymicrobial abdominal sepsis. Additionally, in my preliminary studies, treatment of wild type mice with the GLP-1R agonist liraglutide significantly decreased plasma MCP-1, attenuated organ injury, and increased survival in a model of polymicrobial abdominal sepsis. MCP-1 secretion is regulated by p38 MAPK pathway activation. Interestingly, GLP-1R agonists regulate the activation of MAPK. Therefore, there is rationale that liraglutide inhibits MCP-1 secretion via MAPK regulation. MCP-1 attracts monocytes to the site of inflammation, but also promotes their adhesion by inducing them to upregulate ICAM-1 that is expressed in the activated endothelium. My preliminary data suggests that liraglutide decreases endothelial ICAM expression in vitro. These adhesion molecules allow the attachment of leukocytes to the endothelium and permit their transmigration into peripheral tissue. In Aim 2, I will define the mechanism by which Liraglutide restores the endothelial barrier through downregulation of MCP-1 and the subsequent leukocyte recruitment and tight junction and adherens junction stability. Completion of these aims will determine whether liraglutide attenuates sepsis-induced microvascular permeability and how liraglutide is vasculoprotective through an anti-inflammatory mechanism. This proposal will promote advancement of an endothelial targeted drug to treat sepsis and further my goal to become an independently funded principal investigator studying the mechanisms of endothelial injury in sepsis.


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: 2026 ( Subtotal = $3,000 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Blood Diseases and Resources Research	000	1	4/2/2026	SUPPLEMENT FOR EXPANSION	$3,000
														Subtotal = $3,000

Issue Date FY: 2025 ( Subtotal = $38,654 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Blood Diseases and Resources Research	001	1	7/5/2025	NEW	$0
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Blood Diseases and Resources Research	002	1	7/17/2025	NEW	$564
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Blood Diseases and Resources Research	000	1	1/27/2025	NEW	$38,090
														Subtotal = $38,654

Grand Total All Awards = $41,654

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Attenuation of sepsis-induced microvascular permeability and inflammation with the GLP-1R agonist liraglutide.

Award Number: F31HL178162

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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