Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
基本信息
- 批准号:10534031
- 负责人:
- 金额:$ 3.91万
- 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 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:ATP Synthesis PathwayAcuteAdenine NucleotidesAnoxiaAutomobile DrivingBlood flowCarbonCardiac MyocytesCell RespirationCell physiologyCitric Acid CycleComputer ModelsConsumptionDataDegradation PathwayEnergy MetabolismEnvironmentEnzyme Inhibitor DrugsEnzymesExperimental DesignsExposure toFumaratesGenerationsGoalsHealthHeartHeart MitochondriaHypoxiaImpairmentInfarctionInosine MonophosphateIschemiaKineticsKnock-outLeadMalate-Aspartate Shuttle PathwayMalatesMeasurementMetabolicMetabolismMitochondriaModelingMuscleMyocardialMyocardial ContractionMyocardial InfarctionMyocardial IschemiaMyocardiumOrgan TransplantationOxaloacetatesOxidantsOxidative StressOxidesOxygenPathologicPathway interactionsPlayPreventionProcessProductionPurine NucleotidesPurinesRattusReactionReactive Oxygen SpeciesReperfusion InjuryReperfusion TherapyRoleSuccinate DehydrogenaseSuccinatesSuspensionsSystemTestingTherapeuticTimeTissuesTransgenic OrganismsTransportationUnited StatesVascular blood supplyWorkacronymsalpha ketoglutaratedesignexperimental studyimprovedmetabolomicsmyocardial damagepredictive modelingpreventtargeted treatmenttransplantation therapy
项目摘要
Project Summary/Abstract
The energy utilized by the heart for contractions is primarily made by aerobic respiration. This process consists
of oxidizing carbon substrates to fuel ATP synthesis. An essential substrate is oxygen which acts as the final
electron acceptor. Without oxygen, ATP is rapidly depleted from the myocardium. There are a number of
scenarios where the heart is exposed to hypoxic or anoxic conditions. Ischemia occurs when blood flow becomes
restricted preventing oxygen delivery to part of the muscle. This occurs in ischemic heart disease. If blood flow
is not restored in time, it can lead to irreversible damage, termed myocardial infarction. Organ transplantation is
another scenario where the heart is away from blood supply during transportation. The amount of time the muscle
is without oxygen determines the health of the tissue for the recipient. Situations such as these that involve an
ischemic environment induce metabolic changes that damage the myocardium during reperfusion when oxygen
is restored, known as ischemia-reperfusion injury. One such change is succinate accumulation. During
reperfusion, the immense amount of succinate is responsible for reactive oxygen species (ROS) production that
puts oxidative stress on cardiomyocytes. Another metabolic change seen during ischemia is the depletion of
adenine nucleotides. This group includes AMP, ADP, and ATP and are all essential energy carriers in the
myocardium. The depletion of these molecules results in impaired energy metabolism in the heart. Little is known
about the mechanisms behind these metabolic changes.
The goal of this project is to uncover the primary pathways of succinate accumulation and adenine nucleotide
depletion in ischemic myocardium. The working hypothesis is the combined actions of the tricarboxylic acid
(TCA) cycle, malate-aspartate shuttle (MAS), and the purine nucleotide cycle (PNC) provide the substrate utilized
for succinate production and adenine nucleotides entering the PNC are shuttled into purine degradation
pathways. Experiments involving anoxic isolated heart mitochondrial, ischemic ex vivo hearts, and transgenic
rats will be used jointly with computational models of myocardial metabolism to test this hypothesis. The
metabolic states of these different systems will be quantified by metabolomics and enzyme inhibitors that will be
used to assess primary pathways of accumulation and depletion. Computational models will help with
experimental design, refining, and testing hypotheses. The data from this project will have applications for both
ischemic heart disease, organ transplantation, treatments for ischemia-reperfusion injury.
项目总结/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Nicole Collins其他文献
Nicole Collins的其他文献
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{{ truncateString('Nicole Collins', 18)}}的其他基金
Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
- 批准号:
10794933 - 财政年份:2022
- 资助金额:
$ 3.91万 - 项目类别:
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