The role of Immune-responsive gene 1 and itaconate in atherosclerotic disease
免疫反应基因1和衣康酸在动脉粥样硬化疾病中的作用
基本信息
- 批准号:10607641
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATF2 geneAconitic AcidAcuteAcute DiseaseAgonistAnti-Inflammatory AgentsAntibodiesAortaAreaArterial Fatty StreakArteriesAtherosclerosisCardiovascular DiseasesCardiovascular systemCause of DeathCell physiologyCellsCellular AssayCellular Metabolic ProcessCessation of lifeCholesterolChromatinChronicCitric Acid CycleClassificationClinical TrialsDataDevelopmentEconomic BurdenEnvironmentEnzymesEventFDA approvedFailureGene Expression RegulationGenesIL6 geneImmuneImmune ToleranceIn VitroInfectionInfiltrationInflammasomeInflammationInflammation MediatorsInflammatoryInterferonsInterleukin-1 betaKineticsLDL Cholesterol LipoproteinsLesionLigandsLipidsLipopolysaccharidesLow-Density LipoproteinsMacrophageMeasuresMetabolicMetabolic PathwayMetabolismModalityModificationMusMyeloid CellsMyocardial InfarctionNecrosisPathogenesisPathway interactionsPeptide HydrolasesPermeabilityPharmaceutical PreparationsProductionReactive Oxygen SpeciesRegulationResearchResidual stateRiskRoleSamplingSepsisStimulusStrokeT-LymphocyteTestingTherapeuticTherapeutic EffectThickThrombosisTimeToll-like receptorsTransposaseUp-RegulationWild Type MouseWorkactivating transcription factor 3antimicrobial drugchronic inflammatory diseasecytokineextracellularfeedingimmune activationimmunoregulationin vivoindexinginflammatory markermicrobialmonocytemouse modelneutrophilnovelnovel therapeuticsnuclear factor-erythroid 2overexpressionoxidized low density lipoproteinparticlepatient subsetspreventrecruitsingle-cell RNA sequencingstandard of caresystemic inflammatory responsetargeted treatmenttranscription factortranscriptomewestern diet
项目摘要
PROJECT SUMMARY
Cardiovascular disease (CVD) is the leading cause of death worldwide and represents a significant economic
burden. Atherosclerosis, which is characterized by a build-up of inflammatory lipids and immune cells, is the
most common underlying cause of CVD. Early in the pathogenesis of atherosclerosis, LDL-cholesterol particles
infiltrate the lining of the artery wall, are modified (e.g., oxidized), and activate inflammatory pathways (e.g.,
NLRP3 inflammasome) triggering the production of pro-inflammatory cytokines. A failure to resolve inflammation
within the artery wall leads to the development of a plaque. The current standard of care includes lipid-lowering
drugs such as statins. However, even with successful lipid-lowering, there remains a subset of patients with
residual inflammatory risk. These observations led to several large-scale clinical trials (e.g., CANTOS and Lo-
DoCo2) that targeted systemic inflammation to treat atherosclerotic CVD. These trials demonstrated that target-
ing systemic inflammation reduces adverse cardiovascular events, however, due to an increase in non-cardio-
vascular-related deaths, there are currently no FDA-approved anti-inflammatory therapies for atherosclerosis.
While targeting inflammation systemically has shown promise, it is important to identify more specific targets and
regulators of inflammation within the atherosclerotic plaque to leverage into novel therapies. Research over the
past few decades has established that the metabolic state of the immune cell determines its inflammatory ca-
pacity. As such, rather than targeting systemic inflammation, we propose to leverage the metabolic regulators of
inflammation within the cell. Studies of macrophages stimulated with inflammatory mediators including microbial
ligands and cytokines have revealed significant upregulation of the gene Immune-responsive gene 1 (Irg1, also
Acod1) and its downstream metabolite itaconate. In addition to being an anti-microbial agent, itaconate controls
immune activation and elicits immunological tolerance through (1) regulation of immune cell metabolism, (2)
inhibition of late-stage NLRP3 inflammasome activity, and (3) activation of the anti-inflammatory and anti-oxida-
tive transcription factors Nuclear factor erythroid 2-related factor 2 and Activating transcription factor 3. While
Irg1 and itaconate have been studied in the context of acute inflammation, their role in chronic inflammatory
disease, such as atherosclerosis, has not been explored despite sharing many similar pathways.
In this proposal, I will define the role of Irg1 and itaconate on immune cell regulation in atherosclerosis, specifi-
cally the effects on three major immune cells within the plaque we have found to robustly express Irg1: mono-
cytes, macrophages, and neutrophils. Additionally, I will utilize in vivo mouse models of atherosclerosis to test
whether IRG1 deficiency exacerbates plaque burden and inflammation. Finally, I will elucidate the utility of 4-OI,
a cell-permeable itaconate derivative as a treatment in atherosclerotic CVD. If successful, this will demonstrate
for the first time the role of Irg1 and itaconate in chronic inflammation and identify a novel treatment modality for
the inflammatory component of atherosclerotic CVD.
项目总结
项目成果
期刊论文数量(0)
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