Innate immune pathway activation in endothelial cells by circulating bile acids during atherosclerosis
Active Project Grant Awarded Last action
- Award ID
- F31HL182233
- Recipient
-
University Of California Irvine UEI MJC5FCYQTPE6
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $86,646
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- Irvine, CA 92697, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $43,323 | |
| Amendment | $0 | |
| Original award | $43,323 |
Quick answers
Who received award F31HL182233?
F31HL182233 was awarded to University Of California Irvine by National Heart Lung and Blood Institute (National Institutes of Health) on December 11, 2026.
How much is award F31HL182233 worth?
$86,646 has been obligated on F31HL182233.
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