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Innate immune pathway activation in endothelial cells by circulating bile acids during atherosclerosis

Award Number: F31HL182233
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/11/2026
PERIOD OF PERFORMANCE END DATE: 12/10/2027

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Innate immune pathway activation in endothelial cells by circulating bile acids during atherosclerosis - PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) remains the leading cause of death globally, with atherosclerosis being a primary driver of cardiac events. While inflammation is central to atherosclerosis progression, its upstream triggers and underlying mechanisms remain incompletely understood. The cyclic GMP-AMP synthase (cGAS)- STING pathway, an innate immune sensor of cytosolic DNA, has been implicated in CVD, but its activation mechanisms in vascular endothelial cells remain poorly understood. Our preliminary metabolomic and transcriptomic analysis in LDL receptor knockout pigs, a robust CVD model, demonstrate cGAS-STING activation and downstream inflammation cascades across multiple tissues - accompanied by elevated circulating bile acids. In our endothelial cultures, bile acids induce vascular adhesion molecules downstream of STING at levels comparable to a STING agonist. These results, together with evidence linking bile acids to mitochondrial stress, and the strong association of bile acids with atherosclerosis in humans, suggest that bile acids may activate cGAS-STING in ECs, driving systemic vascular inflammation. This proposal seeks to test the hypothesis that CVD-associated bile acids activate cGAS-STING in endothelial cells, promoting vascular dysfunction and atherosclerosis progression. To test this hypothesis, Aim 1 will define how bile acids activate cGAS-STING signalling in cultured human endothelial cells, including assessing bile acid induced mitochondrial dysfunction and cytosolic DNA release. Aim 2 will establish the physiological relevance of bile acid induced cGAS-STING activation using leukocyte adhesion assays as a functional readout of atherogenesis, and bile acid infusion experiments in endothelial-specific STING knockout mice to evaluate vascular inflammation in vivo. By integrating metabolomics, cell biology, and in vivo models, this study will directly connect metabolic stress to innate immune activation in the vasculature. Defining this mechanism will uncover novel pathways of vascular inflammation in CVD and may identify therapeutic targets to prevent or slow atherosclerosis progression.


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 = $43,323 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cardiovascular Diseases Research	000	1	6/15/2026	NEW	$43,323
														Subtotal = $43,323

Grand Total All Awards = $43,323

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Innate immune pathway activation in endothelial cells by circulating bile acids during atherosclerosis

Award Number: F31HL182233

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/11/2026

PERIOD OF PERFORMANCE END DATE: 12/10/2027

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