Using NAD+ precursor for treatment of global cerebral ischemia
利用NAD前体治疗全脑缺血
基本信息
- 批准号:10294661
- 负责人:
- 金额:$ 38.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylesteraseAcute Brain InjuriesAffectAnimal ModelAnimalsBalanBioenergeticsBrainBrain InjuriesCatabolismCell DeathCell Death ProcessCerebral IschemiaClinicalCognitiveComplexConsumptionDataDeacetylaseDeacetylationDeath RateDoseEmotionalEnzymesEstrous CycleFailureFemaleGenerationsGlutamate-ammonia-ligase adenylyltransferaseGoalsGrantHeart ArrestHistologicImpairmentInjuryIschemiaIschemic Brain InjuryMetabolismMitochondriaMitochondrial ProteinsMusMyocardial InfarctionNerve DegenerationNeurologicNeurological outcomeNeuronsNicotinamide MononucleotidePathologicPathway interactionsPilot ProjectsPoly Adenosine Diphosphate RibosePost-Translational Protein ProcessingProcessProductionProsencephalonProtein AcetylationProteinsProtocols documentationPublishingReactionRecoveryRegulationResearchRoleSIRT1 geneSirtuinsStrokeSurvivorsTestingTherapeuticTimeTransgenic AnimalsTreatment EfficacyTreatment ProtocolsWorkagedaging populationbasebrain cellcell typeclinical applicationcofactorcognitive testingeffective therapyeffectiveness evaluationimprovedinhibitor/antagonistinsightknockout animalmaleneuron lossneuroprotectionpre-clinical researchpreservationprotective effectprotein expressionpsychologicstroke outcomestroke victimstherapy developmenttooltreatment strategy
项目摘要
Summary:
Ischemic brain damage due to cardiac arrest or stroke is one of the most complex pathophysiologic
processes. To successfully treat ischemic brain injury, one need to target several cellular pathways and
cell-type within the brain.
NAD+ is an essential cofactor involved in multiple bioenergetic reactions and its degradation
after ischemia leads to pathologic cellular metabolism and inhibition of energy production. The majority
of cellular NAD+ is re-synthetized via the salvage pathway, where nicotinamide mononucleotide (NMN)
is converted to NAD+. Our recent studies demonstrated that administration of NMN dramatically
ameliorates ischemic brain injury following transient global cerebral ischemia. Furthermore, NMN
treatment inhibited post-ischemic NAD+ catabolism, reduced poly-ADP-ribose generation, and reversed
the excessive mitochondrial fragmentation. Finally, the ischemia-induced changes in mitochondrial
protein acetylation were inhibited in NMN injected animals. Overall goal of this proposed project is to
develop the most effective treatment strategy utilizing NMN that will dramatically reduce ischemic brain
damage and characterize the mechanism of its neuroprotection. We hypothesize that NMN
administration after ischemia will significantly inhibit neurodegeneration due to its multi-targeted effect
and ability to improve mitochondrial functions and cellular bioenergetics.
Specific Aim 1 is focused on the NMN-induced protein acetylation mechanisms that modulate
mitochondrial dynamics and function. The role of Sirt1 and Sirt3 dependent deacetylation in
mitochondrial fusion and fission will be determined using our transgenic animal models that
concomitantly express mitochondria targeted eYFP and Sirt1 or Sirt3. Additionally, SIRT1, and SIRT3
knockout animals will be used as tools for inhibition of deacetylase activity. In specific Aim 2, we will
perform time-dependent studies of NMN administration following global cerebral ischemia in mice. We
will use unbiased stereological quantification of neuronal cell death, and multiple cognitive tests will be
performed to assess the efficacy of treatment. The recovery periods will vary from 7 days up to 6
months after ischemic insult. In specific Aim 3, we will determine the neuroprotective effect of the NMN
treatment by using the most neuroprotective protocol determined in Aim 2 on female and aged animals.
The significance of this work is that it proposes to identify NMN as a protective compound that
will significantly impact the clinical application of NAD+ precursors as therapeutic compounds for acute
brain injury and potentially reveal new targets for neuroprotection.
概括:
心脏骤停或中风引起的缺血性脑损伤是最复杂的病理生理之一
过程。为了成功治疗缺血性脑损伤,需要靶向几个细胞途径和
大脑中的细胞类型。
NAD+是参与多种生物能反应及其降解的必不可少的辅助因子
缺血导致病理性细胞代谢并抑制能量产生。多数
细胞NAD+通过打捞途径重新定位,其中烟酰胺单核苷酸(NMN)
转换为nad+。我们最近的研究表明,NMN的给药很大
瞬时全球脑缺血后,可以改善缺血性脑损伤。此外,NMN
治疗抑制了缺血后NAD+分解代谢,降低了多ADP-核糖的产生,并逆转
线粒体碎片过多。最后,缺血诱导的线粒体变化
NMN注射的动物抑制蛋白乙酰化。这个拟议项目的总体目标是
使用NMN制定最有效的治疗策略,该策略将大大减少缺血性大脑
损害并表征其神经保护的机制。我们假设NMN
缺血后的给药将显着抑制神经退行性因素的多目标作用
以及改善线粒体功能和细胞生物能学的能力。
特定的目标1集中于调节NMN诱导的蛋白乙酰化机制
线粒体动力学和功能。 SIRT1和SIRT3依赖性脱乙酰基的作用在
线粒体融合和裂变将使用我们的转基因动物模型确定
同时表达线粒体靶向EYFP和SIRT1或SIRT3。另外,SIRT1和SIRT3
敲除动物将用作抑制脱乙酰基酶活性的工具。在特定的目标2中,我们将
在小鼠全球脑缺血后,对NMN给药的时间依赖性研究。我们
将使用神经元细胞死亡的公正的立体定量定量,多个认知测试将是
进行评估治疗的功效。恢复期限从7天到6
缺血性侮辱几个月后。在特定目标3中,我们将确定NMN的神经保护作用
通过使用针对女性和老年动物的目标2确定的最神经保护方案的治疗。
这项工作的意义在于,它建议将NMN识别为一种保护性化合物
将显着影响NAD+前体作为急性治疗化合物的临床应用
脑损伤并有可能揭示神经保护的新靶标。
项目成果
期刊论文数量(0)
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{{ truncateString('TIBOR KRISTIAN', 18)}}的其他基金
Using NAD+ precursor for treatment of global cerebral ischemia
利用NAD前体治疗全脑缺血
- 批准号:
10439887 - 财政年份:2021
- 资助金额:
$ 38.63万 - 项目类别:
Using NAD+ precursor for treatment of global cerebral ischemia
利用NAD前体治疗全脑缺血
- 批准号:
10622615 - 财政年份:2021
- 资助金额:
$ 38.63万 - 项目类别:
The role of nicotinamide mononucleotide dependent mitochondrial reactive oxygen species generation in acute brain injury
烟酰胺单核苷酸依赖性线粒体活性氧生成在急性脑损伤中的作用
- 批准号:
10618865 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
The role of nicotinamide mononucleotide dependent mitochondrial reactive oxygen species generation in acute brain injury
烟酰胺单核苷酸依赖性线粒体活性氧生成在急性脑损伤中的作用
- 批准号:
9889770 - 财政年份:2020
- 资助金额:
$ 38.63万 - 项目类别:
The role of nicotinamide mononucleotide dependent mitochondrial reactive oxygen species generation in acute brain injury
烟酰胺单核苷酸依赖性线粒体活性氧生成在急性脑损伤中的作用
- 批准号:
10454777 - 财政年份:2020
- 资助金额:
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9793454 - 财政年份:2019
- 资助金额:
$ 38.63万 - 项目类别:
NAD catabolism and mitochondrial dysfunction in acute neurodegenerative disease
急性神经退行性疾病中 NAD 分解代谢和线粒体功能障碍
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NAD catabolism and mitochondrial dysfunction in acute neurodegenerative disease
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NAD catabolism and mitochondrial dysfunction in acute neurodegenerative disease
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