Modulating mitochondrial calcium in cardiac homeostasis and disease
调节心脏稳态和疾病中的线粒体钙
基本信息
- 批准号:10683219
- 负责人:
- 金额:$ 43.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdrenergic AgentsAdultAffectAnimal ModelAnimalsBasic ScienceCalciumCardiacCardiac MyocytesCardiac healthCause of DeathCell DeathClinicalComplexDataDietDiseaseDisease OutcomeDisease ProgressionEFRACEchocardiographyFatty acid glycerol estersFibrosisFunctional disorderFutureGatekeepingGenesGoalsHeartHeart ContractilitiesHeart failureHistologyHomeostasisHypertensionHypertrophyImpairmentKnowledgeLinkLiteratureMapsMeasuresMediatingMetabolic syndromeMethodologyMissionMitochondriaModelingMolecularMultiprotein ComplexesMusMyocardial dysfunctionNG-Nitroarginine Methyl EsterObesityOperative Surgical ProceduresOrganismOutcomeOutcome AssessmentOutcomes ResearchOxidative StressPathologyPermeabilityPhysiologyPlayProductionProteomicsPublic HealthPumpReportingResearchRespirationRoleSecondary toSignal PathwaySignal TransductionSucroseTamoxifenTestingTherapeuticTimeTissuesUnited States National Institutes of HealthVentricular FunctionWorkaorta constrictiondisabilityfunctional declinegenetic manipulationglucose toleranceheart functionimprovedin vivoinnovationinterestmitochondrial permeability transition poremouse modelnovelpreservationpressureprotein complexprotein expressionresponsetherapeutic developmenttherapy developmenttooluptake
项目摘要
Project Summary/Abstract
A leading cause of death worldwide, heart failure is often linked to deficits in energy production in
mitochondria. Mitochondrial uptake of cytosolic Ca2+ plays a critical role in matching energy production to
demand by stimulating ATP production. However, mitochondrial Ca2+ in excess can lead to permeability
transition pore opening and potentially cell death. Animal models of heart failure more closely akin to heart
failure with reduced ejection fraction (HFrEF) are linked to increased mitochondrial Ca2+ in some studies and
decreased mitochondrial Ca2+ in others; even less is known regarding the role of mitochondrial Ca2+ in heart
failure with preserved ejection fraction (HFpEF). With the long-term goal of helping to develop therapies to limit
or restore mitochondrial Ca2+ when appropriate to improve clinical outcomes in HFrEF and HFpEF, this
application will map out the contribution of increased and decreased mitochondrial Ca2+ to cardiac dysfunction
in homeostasis and in mouse models of pressure overload and high fat/high sucrose diet with L-NAME.
Tamoxifen-inducible cardiac-specific deletion of Micu1, the gene encoding the “gatekeeper” of mitochondrial
Ca2+ uniporter complex (mtCU), will be used to induce mitochondrial Ca2+ overload. In the same manner,
deletion of Emre, the gene encoding the essential regulator of the mtCU, will be used to eliminate mtCU
activity and lower mitochondrial Ca2+. The overall objective in this application is to systematically compare the
effects of increased and decreased mitochondrial Ca2+ on measures of cardiac health – mitochondrial function,
tissue histology, contractility before and after stimulation – in homeostasis and in two different types of induced
heart failure. The central hypothesis is that elevated mtCa2+ impairs heart function in homeostasis and in
HFrEF, whereas lowered mtCa2+ has negative effects in energetically demanding states and in HFpEF. The
rationale is that based on the literature and our preliminary data, pressure overload forces the heart to work
harder, elevating mitochondrial Ca2+, while some indications suggest that mice fed the high fat/high sucrose
diet with L-NAME have lower mitochondrial Ca2+. Hence, in the former conditions, increased mitochondrial
Ca2+ is detrimental, and in the latter, decreased mitochondrial Ca2+ is detrimental. The central hypothesis will
be tested by pursuing two specific aims: 1) Assess how elevated and reduced mitochondrial Ca2+ impact
cardiac homeostasis; and 2) Assess how elevated and reduced mitochondrial Ca2+ impact HFrEF and HFpEF-
MetS. This research is conceptually innovative in using genetic manipulation to modulate mitochondrial Ca2+,
and in directly comparing elevated and reduced mitochondrial Ca2+ in models approximating HFrEF and
HFpEF. The outcomes of this research are expected to be significant by establishing a new paradigm
regarding mitochondrial Ca2+ in HFrEF and HFpEF, with the potential to inform future therapeutic strategies.
项目总结/摘要
心力衰竭是全球死亡的主要原因,通常与心脏能量产生不足有关。
线粒体线粒体对胞质Ca 2+的摄取在使能量产生与细胞内Ca 2+浓度相匹配方面起着关键作用。
刺激ATP的生产。然而,线粒体Ca 2+过量可导致通透性增加,
过渡孔开放和潜在的细胞死亡。心力衰竭的动物模型更接近心脏
在一些研究中,射血分数降低的衰竭(HFrEF)与线粒体Ca 2+增加有关,
在其他人中线粒体Ca 2+减少;关于线粒体Ca 2+在心脏中的作用知之甚少
射血分数保留(HFpEF)。长期目标是帮助开发治疗方法,
或在适当时恢复线粒体Ca 2+以改善HFrEF和HFpEF的临床结局,
应用程序将绘制出线粒体Ca 2+增加和减少对心脏功能障碍的贡献
在稳态和压力超负荷和高脂肪/高糖饮食与L-NAME的小鼠模型中。
他莫昔芬诱导的心肌特异性线粒体“看门人”基因Micu 1缺失
Ca 2+单向转运体复合物(mtCU)将用于诱导线粒体Ca 2+过载。以同样的方式,
缺失编码mtCU基本调节因子的基因Emre将用于消除mtCU
活性和线粒体Ca ~(2+)降低。本申请的总体目标是系统地比较
线粒体Ca 2+增加和减少对心脏健康-线粒体功能测量的影响,
组织组织学,刺激前后的收缩性-稳态和两种不同类型的诱导
心衰核心假设是线粒体Ca 2+升高会损害体内平衡和心功能,
HFrEF,而降低的mtCa 2+在能量需求状态和HFpEF中具有负面影响。的
根据文献和我们的初步数据,压力超负荷迫使心脏工作
更难,升高线粒体Ca 2+,而一些迹象表明,小鼠喂养高脂肪/高糖
添加L-NAME的饲料具有较低的线粒体Ca ~(2+)。因此,在前一种情况下,
Ca 2+是有害的,在后者中,线粒体Ca 2+减少是有害的。核心假设将
通过追求两个具体目标进行测试:1)评估线粒体Ca 2+的升高和降低如何影响
心脏稳态; 2)评估线粒体Ca 2+升高和降低如何影响HFrEF和HFpEF-
MetS。这项研究在利用遗传操作调节线粒体Ca 2+方面具有概念创新性,
以及在接近HFrEF的模型中直接比较线粒体Ca 2+升高和降低,
HFpEF。本研究的成果有望通过建立一个新的范式而产生重大意义
关于HFrEF和HFpEF中的线粒体Ca 2+,有可能为未来的治疗策略提供信息。
项目成果
期刊论文数量(0)
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Julia Chang Liu其他文献
Julia Chang Liu的其他文献
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{{ truncateString('Julia Chang Liu', 18)}}的其他基金
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
10455701 - 财政年份:2020
- 资助金额:
$ 43.83万 - 项目类别:
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
10192800 - 财政年份:2020
- 资助金额:
$ 43.83万 - 项目类别:
Molecular mechanism and physiological function of mitochondrial calcium regulation
线粒体钙调节的分子机制及生理功能
- 批准号:
9370196 - 财政年份:2020
- 资助金额:
$ 43.83万 - 项目类别:
Molecular and physiological analysis of mitochondrial calcium uptake
线粒体钙摄取的分子和生理分析
- 批准号:
9036744 - 财政年份:2015
- 资助金额:
$ 43.83万 - 项目类别:
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