Premature aging disorders, metabolites, and atherosclerosis
Premature aging disorders, metabolites, and atherosclerosis
批准号:
10607893
负责人:
Jun-Ichi Abe
金额:
$75.67万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-12-15 至 2026-11-30
关键词:
AccelerationAgingApoptosisAtherosclerosisCancer SurvivorCardiovascular DiseasesCardiovascular systemCell NucleusCell SeparationChronicCoronary ArteriosclerosisCytometryDNADNA DamageDNA LigationDataDevelopmentDiseaseDoseEndothelial CellsEnzymesEventFeedbackFinding by CauseFunctional disorderGenesGenomic DNAGlutamatesGlycosaminoglycansGoalsHigh Fat DietHumanHydrogen SulfideImageIn VitroIncidenceInflammatoryIonizing radiationIonsKnockout MiceMachine LearningMass ChromatographyMass Spectrum AnalysisMechanicsMediatingMitochondriaModelingMolecularMusOxidation-ReductionPathway AnalysisPathway interactionsPatientsPhenotypePhosphotransferasesPlayPoly(ADP-ribose) PolymerasesPremature aging syndromeProcessProgeriaProtein Kinase CRadiation therapyReactive Oxygen SpeciesRecurrent Malignant NeoplasmReportingResearchResistanceRoleSulfateSyndromeSystemTelomeraseTestingTopoisomeraseTranscriptaseVascular DiseasesWorkattenuationcancer cellcancer recurrenceendothelial dysfunctionin vivoinduced pluripotent stem cellinduced pluripotent stem cell technologyinnovationinsightknowledge basemitochondrial dysfunctionmultiple omicsnew technologynovelnovel strategiesnovel therapeutic interventionoverexpressionprematurepreventrepairedsenescencesugar nucleotidetelomere
中文摘要
项目概要/摘要
电离辐射(IR)诱导的早衰触发血管疾病(PmSVD),以及
如Hutchinson-Gilford早老综合征(HGPS),其显著特征是加速过程
动脉粥样硬化(AthS)和冠状动脉疾病(CAD)。虽然PmSVD中的内皮功能障碍是好的,
已知,缺乏预防PmSVD诱导的CAD的可用治疗;因此,迫切需要
填补这个空白。由TL功能障碍引起的持续性衰老相关分泌表型(PISP),
在癌症复发和耐药性中起核心作用,但其调节机制和对AthS的贡献仍然存在
未知我们的长期目标是确定PmSVD诱导PISP的分子机制。
内皮细胞(EC)和CAD。PmSVD通过激活PKC β显著上调TOP2β降解。的
EC TOP2β的耗竭引起PARP活化和PISP;它还加速AthS。我们展示了
mtROS在PKC β激活中的作用,这是Mt-核反馈回路的初始步骤之一。值得注意的是,
mtROS在IR和HGPS中的关键作用已经被很好地确定。最后,通过在两个样品中进行IC-MS分析,
在IR和HGPS EC中,我们还发现以下3条代谢相关途径在IR和HGPS EC中受到调节
共同的EC:1)核苷酸糖-糖胺聚糖(GAG)和硫酸盐,2)谷氨酸盐,和3)NAD+-
硫化氢(H2S)。尽管所有3种代谢途径对CAD和衰老的贡献已经被证实,
因此,PmSVD在调节PmSVD中的确切作用和机制仍然是未知的。我们建议
PmSVD诱导的线粒体ROS激活PKC β-TOP 2 β模块,随后激活TOP 2 β的新假说
降解,并引发TL DNA损伤。TL DNA损伤促进PARP活化,从而诱导mt
功能障碍并形成线粒体核反馈回路,导致持续的代谢物变化,包括
核苷酸糖和NAD+-H2S途径,导致PISP和CAD。我们将通过追踪
以下3个具体目标:在目标1中,我们将确定以下3个常见的作用和调节机制
体外PmSVD中的代谢物相关途径; 1)核苷酸糖-GAG和硫酸盐,2)谷氨酸盐,3)NAD+-
硫化氢在目的2中,我们将描述PKC β-TOP2β模块和PARP 1在PmSVD介导的代谢物中的作用。
改变和MT功能障碍。在目标3中,我们将确定PKC β-TOP2β模块的作用,
PmSVD诱导的体内冠状动脉AthS(CAthS)中随后的PARP激活。拟议的工作是
预期建立PKC β-TOP2β和PARP作为调节PmSVD诱导的细胞凋亡的中枢分子的作用。
代谢物变化和PISP。这种方法是创新的,因为我们将使用iPSC,离子等新技术。
色谱-质谱(IC-MS),机器学习,成像质谱细胞术,和一种新的小鼠
CAthS模型。拟议的研究应该通过导致一种新的方法来积极影响PmSVD,
抑制PISP。
英文摘要
Project Summary/Abstract
Premature senescence-triggered vascular diseases (PmSVD) induced by ionizing radiation (IR), as well
as Hutchinson-Gilford progeria syndrome (HGPS), are notably characterized by accelerating processes
of atherosclerosis (AthS) and coronary artery disease (CAD). Although endothelial dysfunction in PmSVDs is well
known, there is a paucity of available treatments to prevent PmSVD-induced CAD; hence, there is an urgent need to
fill this gap. Persistent senescence-associated secretory phenotype (PISP), provoked by TL dysfunction, plays a
central role in cancer recurrence and resistance, but its regulatory mechanisms and contribution to AthS remain
unknown. Our long-term goal is to determine the molecular mechanisms by which PmSVD induces PISP in
endothelial cells (ECs) and CAD. PmSVD significantly up-regulated TOP2β degradation via PKCζ activation. The
depletion of EC TOP2β instigated PARP activation and PISP; it also accelerated AthS. We showed the critical
role of mtROS in PKCζ activation, which is one of the initial steps for the Mt-nucleus feedback loop. Of note, the
crucial role of mtROS in both IR and HGPS has been well established. Lastly, by performing IC-MS analysis in both
IR and HGPS ECs, we also found that the following 3 metabolite-related pathways were regulated in IR and HGPS
ECs in common: 1) nucleotide sugars-glycosaminoglycans (GAGs) and sulfate, 2) glutamate, and 3) NAD+-
hydrogen sulfide (H2S). Although the contribution of all 3 metabolites pathways to CAD and aging has been
suggested, the exact role and mechanical insights in regulating PmSVD remain largely unknown. We propose the
novel hypothesis that PmSVD-induced mtROS activates the PKCζ-TOP2β module, followed by TOP2β
degradation, and instigates TL DNA damage. TL DNA damage promotes PARP activation, which induces mt
dysfunction and forms an mt-nucleus feedback loop, resulting in persistent metabolites changes, including
nucleotide sugars and NAD+-H2S pathways, causing PISP and CAD. We will test our hypothesis by pursuing the
following 3 specific aims: In Aim 1, we will determine the role and regulatory mechanisms of the following 3 common
metabolites-related pathways in PmSVD in vitro; 1) nucleotide sugars-GAGs and sulfate, 2) glutamate, 3) NAD+-
H2S. in Aim 2, we will characterize the role of PKCζ-TOP2β module and PARP1 in PmSVD-mediated metabolites
changes and mt dysfunction in vitro. In Aim 3, we will determine the role of the PKCζ-TOP2β module and
subsequent PARP activation in PmSVD-induced coronary AthS (CAthS) in vivo. The proposed work is
expected to establish the roles of PKCζ-TOP2β and PARP as the hub molecules in regulating PmSVD-induced
metabolite changes and PISP. The approach is innovative because we will use the new technologies of iPSC, ion
chromatography-mass spectrometry (IC-MS), machine learning, imaging mass cytometry, and a novel mouse
CAthS model. The proposed research should positively impact PmSVD by leading to a novel approach to
inhibiting PISP.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10425386
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PAR 13-233 cART accelerates vascular aging in HIV infected subjects
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PAR 13-233 cART accelerates vascular aging in HIV infected subjects
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海外基金