Myocardial Infarct in Aging Animals and dATP Therapy
老龄动物心肌梗死和 dATP 治疗
基本信息
- 批准号:9565690
- 负责人:
- 金额:$ 68.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-30 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAffectAgeAgingAnimal ModelAnimalsBindingBiological AssayCanis familiarisCardiacCardiac MyocytesCellsCoupledDataDevelopmentDilated CardiomyopathyElderlyEnzymesExercise ToleranceFamily suidaeFatigueFunctional disorderGoalsHealthHealth BenefitHealth Care CostsHeartHeart failureHome Nursing CareHumanImpairmentInfarctionKineticsLeadLeftLeft Ventricular FunctionLifeLongevityMeasuresMediatingMetabolicMetabolismMitochondriaModelingMorphologyMusMuscleMuscle WeaknessMuscle functionMyocardial InfarctionMyocardiumMyofibrilsMyopathyMyosin ATPaseNucleotidesOrganPathologicPatientsPerformancePerformance at workPhysiologyPopulations at RiskPreparationPropertyProtein IsoformsProteomicsPublic HealthQuality of lifeRelaxationReportingResistanceRespirationRibonucleotide ReductaseRiskRodentRoleRunningSkeletal MuscleSkeletal Muscle MyosinsSkinSpeedStriated MusclesSystemTestingTissuesTransgenic OrganismsVentricularViralViral VectorWorkadeno-associated viral vectorage relatedagedaging populationexercise capacityexercise intoleranceexperimental studygene therapyheart functionheart metabolismimprovedimproved mobilityinterdisciplinary approachjuvenile animalmature animalmetabolic profilemetabolomicsmuscle agingmuscle metabolismnovelnovel therapeuticsnucleotide metabolismolder patientoverexpressionpromoterresistance exerciseresponseskeletaltreadmillvectoryoung adult
项目摘要
ABSTRACT The goal of this project is two-fold: 1) to determine how age compounds the effect of myocardial
infarct (MI) on heart function and how this affects skeletal muscle function and exercise tolerance; and 2) to
determine the ability of 2 deoxy-ATP (dATP) to affect heart and skeletal muscle performance, metabolism and
exercise tolerance in age and MI induced heart failure. Most studies of performance decline with MI are done
with young animal models, to look at infarct specific effects. However, MI occurs most often in the elderly, and
it is not clear the extent to which this compounds pathologic effects at the system, organ and cell levels. Thus,
we will study how age impacts the effects of MI on heart and skeletal muscle contractile and metabolic function.
We will then use this model to study cardiac-specific vs. cardiac + skeletal muscle elevation of dATP. We have
previously reported that dATP enhances contraction in demembranated cardiac and skeletal muscle by
increasing myosin binding to actin (crossbridge formation) and crossbridge cycling. We have also reported that
cellular levels of dATP can be elevated in the heart and skeletal muscle via transgenic or viral vector-mediated
or over-expression of the enzyme Ribonucleotide Reductase (RNR). Both of these approaches enhance left
ventricular (LV) heart function and increases the magnitude and speed of cardiomyocyte contraction & relaxation
in normal hearts and rescues LV function of infarcted hearts of rodents and pigs. These previous MI studies
were done in young adult animal and we did not determine how cardiac-specific elevation of dATP affected
skeletal muscle or exercise tolerance. In preliminary data we demonstrate that 1) both demembranated cardiac
and skeletal muscle from old mice have enhanced contraction when dATP (vs. ATP) is the substrate for
contraction, 2) transgenic young mice with elevated heart and skeletal muscle [dATP] have greater exercise
capacity, faster treadmill running and fatigue resistance, and 3) elevated cardiac RNR and dATP may protect
against transition from an oxidative to glycolytic cardiac metabolic profile following MI (in young mice) and rescue
this `more youthful' oxidative profile in old mice. In the proposed experiments we will determine if AAV-RNR
vectors can improve cardiac and skeletal muscle performance, exercise capacity and metabolic performance of
old mice with and without MI. We will compare vectors with cardiac-specific vs. striated muscle-specific
expression of RNR. Thus our proposal offers a unique model to study how specifically targeting the heart to
improve its performance can have secondary beneficial effects in skeletal muscle. Function will be measured at
whole organ, cell and myofibril levels for both cardiac and skeletal muscle and coupled with measures of
metabolic efficiency and activity, mitochondrial function, and metabolomics and proteomic analysis. This multi-
scale analysis, using interdisciplinary approaches, will provide information for mechanistic interpretations. The
results from these studies will determine feasibility of our approach (AAV-RNR mediated elevation of dATP in
muscle) for treatment of heart failure and other age-related declines in cardiac function and exercise tolerance.
摘要 该项目的目标有两个:1)确定年龄如何复合心肌的影响
梗塞(MI)对心脏功能的影响以及它如何影响骨骼肌功能和运动耐量; 2) 至
确定 2 脱氧 ATP (dATP) 影响心脏和骨骼肌性能、代谢和
年龄和心肌梗死引起的心力衰竭的运动耐量。大多数关于 MI 导致的表现下降的研究已经完成
使用年轻的动物模型来观察梗塞的具体影响。然而,心肌梗死最常发生在老年人中,并且
目前尚不清楚这种现象在多大程度上会在系统、器官和细胞水平上产生病理影响。因此,
我们将研究年龄如何影响心肌梗死对心脏和骨骼肌收缩和代谢功能的影响。
然后,我们将使用该模型来研究心脏特异性与心脏 + 骨骼肌 dATP 升高。我们有
先前报道,dATP 通过以下方式增强去膜心肌和骨骼肌的收缩:
增加肌球蛋白与肌动蛋白的结合(横桥形成)和横桥循环。我们还报道过
通过转基因或病毒载体介导,可以提高心脏和骨骼肌中 dATP 的细胞水平
或核糖核苷酸还原酶(RNR)的过度表达。这两种方法都增强了左
心室 (LV) 心脏功能并增加心肌细胞收缩和舒张的幅度和速度
在正常心脏中,并挽救啮齿动物和猪梗塞心脏的左心室功能。这些先前的 MI 研究
是在年轻的成年动物中进行的,我们没有确定 dATP 的心脏特异性升高如何影响
骨骼肌或运动耐力。在初步数据中,我们证明 1) 脱膜心脏
当 dATP(相对于 ATP)作为底物时,年老小鼠的骨骼肌收缩增强
收缩,2) 心脏和骨骼肌 [dATP] 升高的转基因年轻小鼠有更大的运动量
能力、更快的跑步机跑步和抗疲劳能力,以及 3) 升高的心脏 RNR 和 dATP 可以保护
防止心肌梗塞(年轻小鼠)和救援后从氧化向糖酵解心脏代谢特征的转变
年老小鼠的这种“更年轻”的氧化特征。在建议的实验中,我们将确定 AAV-RNR 是否
载体可以改善心肌和骨骼肌的性能、运动能力和代谢性能
有和没有心肌梗死的老小鼠。我们将比较心脏特异性载体与横纹肌特异性载体
RNR 的表达。因此,我们的建议提供了一个独特的模型来研究如何专门针对心脏
提高其性能可以对骨骼肌产生次要的有益影响。函数将在以下位置测量
心肌和骨骼肌的整个器官、细胞和肌原纤维水平,并结合以下指标的测量
代谢效率和活性、线粒体功能以及代谢组学和蛋白质组学分析。这个多
使用跨学科方法的规模分析将为机械解释提供信息。这
这些研究的结果将确定我们的方法的可行性(AAV-RNR 介导的 dATP 升高)
肌肉)用于治疗心力衰竭和其他与年龄相关的心功能和运动耐量下降。
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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{{ truncateString('MICHAEL REGNIER', 18)}}的其他基金
Bioengineering Cardiovascular Training Grant (BCTG)
生物工程心血管培训补助金 (BCTG)
- 批准号:
10418471 - 财政年份:2022
- 资助金额:
$ 68.26万 - 项目类别:
Bioengineering Cardiovascular Training Grant (BCTG)
生物工程心血管培训补助金 (BCTG)
- 批准号:
10650834 - 财政年份:2022
- 资助金额:
$ 68.26万 - 项目类别:
EFFECT OF R1R2 OVER-EXPRESSION ON CARDIAC FUNCTION
R1R2 过度表达对心脏功能的影响
- 批准号:
8891479 - 财政年份:2012
- 资助金额:
$ 68.26万 - 项目类别:
EFFECT OF R1R2 OVER-EXPRESSION ON CARDIAC FUNCTION
R1R2 过度表达对心脏功能的影响
- 批准号:
8529267 - 财政年份:2012
- 资助金额:
$ 68.26万 - 项目类别:
EFFECT OF R1R2 OVER-EXPRESSION ON CARDIAC FUNCTION
R1R2 过度表达对心脏功能的影响
- 批准号:
8708949 - 财政年份:2012
- 资助金额:
$ 68.26万 - 项目类别:
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