Hexokinase-II protects the heart against ischemia through regulation of autophagy
己糖激酶-II 通过调节自噬保护心脏免受缺血
基本信息
- 批准号:9130407
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-04 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectApoptoticAutophagocytosisBindingBiological PreservationCardiacCardiac MyocytesCell DeathCell SurvivalCellsCo-ImmunoprecipitationsComplexDataDependovirusDevelopmentDissociationEnergy-Generating ResourcesFluorescence Resonance Energy TransferGap JunctionsGlucoseGlycolysisGoalsHealthHeartHeart DiseasesHexokinase 2InjuryIschemiaLinkLocationLysosomesMediatingMetabolicMetabolismMethodsMitochondriaMolecularMorbidity - disease rateMusMyocardial InfarctionMyocardial IschemiaN-terminalNecrosisOrganOrganellesOxidative StressPathway interactionsPeptidesPhosphorylationPlayProductionProtein IsoformsPublishingRegulationReperfusion InjuryRoleSerotypingSignal PathwaySignal TransductionSiteStarvationStressSystemTechniquesTestingTherapeutic InterventionTransgenic MiceTransgenic OrganismsUbiquitinationbasedeprivationglucose metabolismhexokinasein vivomTOR proteinmitochondrial autophagymortalitymutantparkin gene/proteinreceptorresearch studyresponsevector
项目摘要
DESCRIPTION (provided by applicant): The heart is a high-energy demand organ and ischemic heart disease is a significant cause of morbidity and mortality. During ischemia, macroautophagy (hereafter referred to as autophagy) is induced to sequester intracellular contents and organelles including mitochondria for lysosomal degradation resulting in preservation of cellular energy status and conferring cell survival. Mitochondrial autophagy (mitophagy) is a selective type of autophagy which also plays a protective role by eliminating compromised mitochondria, thereby limiting the activation of mitochondrial cell death pathways as well as supplying an energy source. Hexokinase-II (HK-II) catalyzes the first step of glycolysis, phosphorylating glucose, and is the predominant isoform in the heart. HK-II is increasingly recognized as a survival signaling nexus, especially as a protective molecule at mitochondria against acute oxidative stress such as reperfusion injury. Building on our recently published and preliminary data, this study will examine a new facet of HK-II survival signaling: the coordination of metabolic status with mitophagy and autophagy to enhance cell survival during metabolic suppression. Aim 1 will determine whether dissociation mitochondrial HK-II (mitoHK-II) plays a regulatory role in recognition of damaged mitochondria to limit cardiac damage induced by ischemia in cardiomyocytes using adenoviral expression of mitoHK-II dissociating peptide (15NG). We will determine whether HK-II binds to mitofusin-2, Parkin receptors at mitochondria to regulate mitophagy. In Aim 2, we will determine whether HK-II regulates non-selective autophagy during ischemia in cardiomyocytes. Based on our recent study, we hypothesize that HK-II binds to and inhibits mTOR complex 1 (TORC1) to increase protective autophagy under ischemia and that this binding occurs at lysosome, a TORC1 activation site, in response to energy depletion. In Aim 3, we will determine whether mitophagic and autophagic effects of HK- II emerged during ischemia play a protective role against ischemic stress in vivo heart using 15NG transgenic mice generated in the lab as well as in vivo expression of HK-II mutants using adeno-associated virus serotype 9 (AAV9) technique. The long term goal of this proposal is to unveil a previously unrecognized link between HK-II and protective autophagy as a potential target for therapeutic intervention in heart diseases.
描述(申请人提供):心脏是高能量需求器官,缺血性心脏病是发病率和死亡率的重要原因。缺血时,诱导巨噬(以下简称自噬)隔离细胞内内容物和包括线粒体在内的细胞器进行溶酶体降解,从而保存细胞能量状态并保证细胞存活。线粒体自噬(mitophagy)是一种选择性自噬,通过消除受损的线粒体发挥保护作用,从而限制线粒体细胞死亡途径的激活,并提供能量来源。己糖激酶ii (HK-II)催化糖酵解的第一步,磷酸化葡萄糖,是心脏中的主要亚型。HK-II被越来越多地认为是一种生存信号通路,特别是作为线粒体抗急性氧化应激(如再灌注损伤)的保护分子。基于我们最近发表的和初步的数据,本研究将研究HK-II生存信号的一个新的方面:代谢状态与线粒体自噬和自噬的协调,以提高代谢抑制期间的细胞存活。Aim 1将通过腺病毒表达mitoHK-II解离肽(15NG)来确定解离线粒体HK-II (mitoHK-II)是否在识别受损线粒体中发挥调节作用,以限制心肌细胞缺血引起的心脏损伤。我们将确定HK-II是否与线粒体中的Parkin受体mitofusin-2结合以调节线粒体自噬。在Aim 2中,我们将确定HK-II是否调节心肌细胞缺血时的非选择性自噬。根据我们最近的研究,我们假设HK-II结合并抑制mTOR复合物1 (TORC1)以增加缺血下的保护性自噬,并且这种结合发生在溶酶体(TORC1的激活位点)上,以响应能量消耗。在Aim 3中,我们将利用实验室培养的15NG转基因小鼠,以及利用腺相关病毒血清型9 (AAV9)技术在体内表达HK-II突变体,确定在缺血期间出现的HK-II有丝分裂和自噬作用是否对体内心脏缺血应激起到保护作用。本研究的长期目标是揭示先前未被认识到的HK-II与保护性自噬之间的联系,作为心脏病治疗干预的潜在靶点。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nutrient-sensing mTORC1: Integration of metabolic and autophagic signals.
- DOI:10.1016/j.yjmcc.2016.01.005
- 发表时间:2016-06
- 期刊:
- 影响因子:5
- 作者:Tan VP;Miyamoto S
- 通讯作者:Miyamoto S
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Shigeki Miyamoto其他文献
Shigeki Miyamoto的其他文献
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{{ truncateString('Shigeki Miyamoto', 18)}}的其他基金
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
- 批准号:
8269124 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
- 批准号:
8469356 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
- 批准号:
7900315 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
- 批准号:
7699508 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
Mitochondrial Protection by Hexokinase-II and Akt in the Heart
己糖激酶 II 和 Akt 对心脏的线粒体保护
- 批准号:
8094522 - 财政年份:2009
- 资助金额:
$ 38.75万 - 项目类别:
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