PERM in Cardiac Function
PERM 对心脏功能的影响
基本信息
- 批准号:10320398
- 负责人:
- 金额:$ 39.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAgeAnimal ModelBiochemicalBioenergeticsBiogenesisBiologyBreedingCardiacCardiac MyocytesCell RespirationChronicComplexCoronaryDataDevelopmentDilated CardiomyopathyDiseaseERR1 proteinEnergy MetabolismEstrogen Nuclear ReceptorEvolutionFutureGene ExpressionGenesGenetic TranscriptionHandHeartHeart DiseasesHeart MitochondriaHeart failureHumanHypertrophyIschemiaKnock-outLeadLearningLigationMediatingMetabolicMetabolic PathwayMetabolismMicroscopyMitochondriaMitochondrial DNAModelingMolecularMorbidity - disease rateMusMuscleMuscle FibersMuscle functionMutationMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumNuclearOrganismOrphanOxygenPPAR gammaPathway interactionsPatientsPhysiologicalPhysiologyPlayProductionProteinsPublishingReceptor SignalingRegulationReperfusion InjuryReperfusion TherapyRoleSignal TransductionSkeletal MuscleStressStriated MusclesTestingTissuesTransgenic OrganismsWorkbasecardiogenesiscardioprotectionconstrictionemerging adultestrogen-related receptorgenome-wide analysisheart functionheart metabolismhemodynamicshuman modelimprovedin vivoinnovationischemic cardiomyopathyischemic injurymetabolic abnormality assessmentmetabolomicsmitochondrial dysfunctionmortalitymouse modelmuscle metabolismmyocardial damagenew therapeutic targetnovelnovel strategiesnovel therapeuticsoverexpressionoxidative damagepressurepreventreduce symptomsrespiratoryresponsetranscription factor
项目摘要
Cardiac contraction requires a high and reliable flux of ATP as energetic deficiencies lead to disease, as seen
in humans with mutations in mitochondrial DNA or nuclear-encoded respiratory genes. This is supported by
mouse models with mutations in genes of oxidative metabolism. Cardiac energy metabolism and, in particular,
the high capacity for ATP production are controlled by a network of transcriptional regulators, including the
coactivators PGC-1 and PGC-1, and the orphan nuclear receptors ERR and ERR. This network regulates
genes important for mitochondrial biogenesis, oxidative metabolism and thus contraction of cardiac myocytes
(CM). PGC-1/ ERR complexes act directly on many target genes, but also activate downstream transcription
factors that amplify and/or extend their scope of action. Elucidation of such PGC-1/ERR downstream effectors
can reveal novel molecules that impact heart bioenergetics and that could be used to beneficially modify
cardiac energy state. Here, we will elucidate the role of a novel gene, PERM1, in cardiac energy
metabolism. We identified it as a gene induced by PGC-1/ and ERR//and found it expressed
specifically in tissues with high-energy demand, such as heart and skeletal muscle, and induced in vivo by
signals known to activate PGC-1. We hypothesize that PERM1 acts with PGC-1 and ERR factors in
controlling the expression of genes important for mitochondrial biogenesis and ATP production,
thereby protecting the heart from heart failure induced by pressure overload and ischemia reperfusion
injury. Three aims will test this hypothesis: Aim 1. Study of the metabolic pathways regulated by Perm1 in
cardiomyocytes (CM). This aim will study metabolic pathways regulated by Perm1 in cultured CM to evaluate
the hypothesis that Perm1 modulates Mito biogenesis and cellular metabolic pathways in the CM. It will pursue
the involvement of PGC-1/ERR in Perm1 function, and also evaluate mechanism(s) by which Perm1
modulates PGC-1/ERR activity using directed and unbiased approaches, including metabolomics. Aim 2.
Determine the role of Perm1 in pressure overload-induced HF. We will focus on the role of Perm1 in the
heart subjected to hemodynamic stress, and assess its role as the heart undergoes evolution from
compensated hypertrophy to HF. For this we use mouse models (in hand) which direct CM-specific
overexpression and ablation (knockout (KO)) of Perm1 expression – (termed Perm1cTg and Perm1cKO,
respectively). Aim 3. Evaluate the role of Perm1 in providing cardiac protection from deleterious effects
of ischemia and ischemia-reperfusion (IR) injury. We will study the role of Perm1 in ischemic injury also
using our unique mouse models, given the hypothesis that Perm1cTG-mediated overexpression will be
cardioprotective in the ischemic heart, while Perm1cKO will produce deleterious responses in ischemic-
challenged hearts. We expect this work to define PERM1 as a regulator of cellular bioenergetics and
potentially provide a new target for therapeutic pathways that are applicable to treatment of heart failure.
心脏收缩需要高而可靠的三磷酸腺苷流量,因为能量缺乏会导致疾病,如图所示
在线粒体DNA或核编码呼吸基因突变的人类中。这是由支持的
氧化代谢基因突变的小鼠模型。心脏能量代谢,尤其是,
ATP的高生产能力由转录调控网络控制,包括
辅活化子pGC-1和pGC-1,以及孤儿核受体Err和Err。这个网络规范着
线粒体生物发生、氧化代谢和心肌细胞收缩的重要基因
(厘米)。PGC-1/ERR复合体不仅直接作用于许多靶基因,而且还激活下游转录
扩大和/或扩大其行动范围的因素。PGC-1/ERR下游效应因子的研究进展
可以揭示影响心脏生物能量学的新分子,并可用于有益地修改
心脏能量状态。在这里,我们将阐明一种新的基因PERM1在心脏能量中的作用
新陈代谢。我们鉴定它是由pGC-1/和ERR//诱导的一个基因,并发现它表达
特别是在具有高能量需求的组织中,如心脏和骨骼肌,并在体内由
已知的激活pGC-1的信号。我们假设PERM1与PGC-1和ERR因子一起作用于
控制对线粒体生物发生和ATP生产至关重要的基因的表达,
从而保护心脏免受压力超负荷和缺血再灌流引起的心力衰竭
受伤。三个目标将验证这一假说:目标1.Perm1调节的代谢途径的研究
心肌细胞(CM)。本研究的目的是研究Perm1在培养的CM中调节的代谢途径,以评估
Perm1在CM中调节有丝分裂生物发生和细胞代谢途径的假说。它将继续追查
PGC-1/ERR在Perm1功能中的作用及其机制探讨(S)
使用定向和无偏见的方法,包括代谢组学,调节PGC-1/ERR的活性。目标2.
确定Perm1在压力超负荷诱导的心衰中的作用。我们将重点介绍Perm1在
心脏受到血流动力学应激,并评估其在心脏经历从
代偿性肥大转为心衰。为此,我们使用鼠标模型(在手中),它指示特定于CM的
Perm1表达的过表达和消融(敲除(KO))-(称为Perm1cTg和Perm1cKO,
)。目的3.评价Perm1在保护心脏免受有害影响方面的作用
缺血和缺血-再灌流(IR)损伤。我们还将研究Perm1在缺血损伤中的作用
使用我们独特的小鼠模型,假设Perm1cTG介导的过度表达将是
Perm1cKO在缺血心脏中具有心脏保护作用,而Perm1cKO在缺血心脏中会产生有害反应。
挑战的心脏。我们希望这项工作将PERM1定义为细胞生物能量学的调节因子,并
有可能为治疗心力衰竭的治疗途径提供一个新的靶点。
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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Yoshitake Cho其他文献
Yoshitake Cho的其他文献
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{{ truncateString('Yoshitake Cho', 18)}}的其他基金
The role of obscurin and Obsl1 as key determinants for diastolic function
Obscurin 和 Obsl1 作为舒张功能关键决定因素的作用
- 批准号:
10334533 - 财政年份:2021
- 资助金额:
$ 39.5万 - 项目类别:
The role of obscurin and Obsl1 as key determinants for diastolic function
Obscurin 和 Obsl1 作为舒张功能关键决定因素的作用
- 批准号:
10554438 - 财政年份:2021
- 资助金额:
$ 39.5万 - 项目类别:
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