A hypercholesterolemia-induced immunometabolite in atherosclerosis
高胆固醇血症诱导的动脉粥样硬化免疫代谢物
基本信息
- 批准号:10343505
- 负责人:
- 金额:$ 69.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:Arterial Fatty StreakAtherosclerosisAttentionCardiovascular DiseasesCessation of lifeCholesterolChronicChronic DiseaseCoronary heart diseaseDNA Modification ProcessDataDevelopmentDioxygenasesEndoplasmic ReticulumEpigenetic ProcessEtiologyEukaryotic Initiation FactorsFamilyGenesGenetic ModelsHumanHyperlipidemiaHypoxiaIn VitroInflammasomeInflammationInflammatoryInflammatory ResponseKnock-inKnowledgeLinkLipidsLiteratureMalignant NeoplasmsMediatingMediator of activation proteinMembraneMetabolicMetabolic PathwayMethylationMitochondriaMusMyelogenousMyeloid CellsMyocardial InfarctionMyocardial dysfunctionOnset of illnessOrganellesOxidoreductasePathway interactionsPhosphoglycerate dehydrogenasePhosphorylationPhosphotransferasesProductionProtein DephosphorylationRecoveryRoleSaturated Fatty AcidsSignal TransductionSignaling MoleculeSomatic MutationSterilityStimulusStressStress Response SignalingSupplementationTherapeuticToxic effectTranslationsTreatment EfficacyWorkactivating transcription factor 1activating transcription factor 4alpha ketoglutarateantagonistatherogenesisbasebiological adaptation to stresscofactorearly onsetendoplasmic reticulum stressepigenomegenetic approachhypercholesterolemiain vivoinsightmacrophagenew therapeutic targetnovel therapeuticsoxidationpreventresponsesmall moleculetherapeutic targettranscriptomevascular inflammation
项目摘要
PROJECT ABSTRACT
A maladaptive inflammatory response to lipid imbalance underlies the chronic vascular inflammation in
atherosclerosis. Persistent activation of the Integrated Stress Response (ISR) signaling is also observed in both
mouse and human atheroma. ISR is an elaborate, homeostatic signaling activated by a range of conditions such
as hypoxia, hyperlipidemia and endoplasmic reticulum (ER) and mitochondrial stress, which are known to
promote atherosclerosis. Small molecules and genetic models that prevent hypercholesterolemia-induced ISR
signaling were shown to prevent atherosclerosis progression, demonstrating ISR’s causality in atherosclerosis
development. Despite regulating lipid-induced sterile inflammation, thereby representing a novel therapeutic
opportunity in cardiovascular disease (CVD), therapeutic targeting of a homeostatic pathway such as ISR in a
chronic disease is not without its challenges. Deciphering the detailed mechanisms by which ISR governs
macrophage immunometabolism and atherogenesis can pave the way to effective and specific therapeutic
strategies in CVD while escaping toxicity that may be associated with targeting homeostatic signaling. We made
the striking discovery that ISR inhibition in hypercholesterolemic mice leads to increased 5-
hydroxymethylcytosine (5-hmC) to 5-methylcytosine (5-mC) ratio in macrophages and plaques while reducing
IL-1b and atherosclerosis progression. The oxidation of 5-mC to 5-hmC is catalyzed by Ten eleven translocation
(TET) family of methylcytosine dioxygenases, somatic mutations in which are associated with coronary heart
disease and early-onset myocardial infarction (MI). The inactivation of TET-2 in mice promotes atherosclerosis
progression and cardiac dysfunction. Our robust preliminary data shows that hypercholesterolemia induces 2-
hydroxyglutarate (2HG), a potent TET inhibitory metabolite, in an ISR-dependent manner. Furthermore,
supplementation with a-ketoglutarate (aKG), a cofactor for TET, stimulates TET activity while inhibiting IL-1b
secretion in mouse and human macrophages. aKG supplementation in a small group of hypercholesterolemic
mice prevented inflammation while reversing TET inhibition. Building on the insight gained through our robust
preliminary studies and incorporating additional evidence from literature, we hypothesize that hyperlipidemia-
induced ISR signaling generates an immunometabolite that can promote macrophage inflammatory
response and atherosclerosis. We propose to investigate ATF4’s role in regulating macrophage
immunometabolism and promoting atherosclerosis in vivo. We will also investigate the consequences of
modulating 2HG levels in myeloid cells on inflammation and atherosclerosis in hypercholesterolemic mice. The
completion of the proposed studies will illuminate the metabolic and epigenetic consequences for ISR signaling
in macrophages on sterile inflammation and atherosclerosis development. The new knowledge gained through
these studies could pave the way for the development of effective and specific therapeutic strategies to
antagonize ISR signaling components that promote sterile inflammation and drive atherosclerosis progression.
项目摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Prediman Krishan Shah其他文献
Management of Aminotransferase Elevations Observed in a Phase 3 Study of Patients with Homozygous Familial Hypercholesterolemia Treated with Lomitapide
- DOI:
10.1016/j.jacl.2013.03.058 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Marina Cuchel;Emma A. Meagher;Prediman Krishan Shah;LeAnne T. Bloedon;Daniel J. Rader; Phase 3 HoFH Lomitapide Study Investigators - 通讯作者:
Phase 3 HoFH Lomitapide Study Investigators
Apheresis Treatment did not Impact the Efficacy of Lomitapide in Patients with Homozygous Familial Hypercholesterolemia: Results from the Pivotal Phase†
- DOI:
10.1016/j.jacl.2013.03.095 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Marina Cuchel;Emma A. Meagher;Prediman Krishan Shah;LeAnne T. Bloedon;Daniel J. Rader; Phase 3 HoFH Lomitapide Study Investigators - 通讯作者:
Phase 3 HoFH Lomitapide Study Investigators
Multiple myocardial crypts on cardiac CT angiography in a symptomatic patient with troponin elevation
- DOI:
10.1016/j.ijcard.2011.01.020 - 发表时间:
2011-11-17 - 期刊:
- 影响因子:
- 作者:
Rine Nakanishi;Ronak Rajani;Haim Shmilovich;Prediman Krishan Shah;Daniel S. Berman - 通讯作者:
Daniel S. Berman
Prediman Krishan Shah的其他文献
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{{ truncateString('Prediman Krishan Shah', 18)}}的其他基金
The role of GATA3-positive macrophages in cardiovascular pathologies
GATA3 阳性巨噬细胞在心血管病理中的作用
- 批准号:
10643888 - 财政年份:2022
- 资助金额:
$ 69.41万 - 项目类别:
A hypercholesterolemia-induced immunometabolite in atherosclerosis
高胆固醇血症诱导的动脉粥样硬化免疫代谢物
- 批准号:
10532799 - 财政年份:2021
- 资助金额:
$ 69.41万 - 项目类别:
AAV MEDIATED APO A1 GENE THERAPY FOR ATHEROSCLEROSIS
AAV 介导的 APO A1 基因治疗动脉粥样硬化
- 批准号:
6575135 - 财政年份:2002
- 资助金额:
$ 69.41万 - 项目类别:
AAV MEDIATED APO A1 GENE THERAPY FOR ATHEROSCLEROSIS
AAV 介导的 APO A1 基因治疗动脉粥样硬化
- 批准号:
6338900 - 财政年份:2000
- 资助金额:
$ 69.41万 - 项目类别:
AAV MEDIATED APO A1 GENE THERAPY FOR ATHEROSCLEROSIS
AAV 介导的 APO A1 基因治疗动脉粥样硬化
- 批准号:
6189142 - 财政年份:1999
- 资助金额:
$ 69.41万 - 项目类别:
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