The role of redox balance in cyanide toxicity and mitochondrial disease
氧化还原平衡在氰化物毒性和线粒体疾病中的作用
基本信息
- 批准号:10782976
- 负责人:
- 金额:$ 3.73万
- 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 2025-08-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAftercareAgeAntidotesAssociation LearningBehavioralBindingBiological AssayBirthBrainCellsCharacteristicsCollectionComplexConsumptionCyanidesCytosolDeacetylaseDeacetylationDiseaseElectron TransportElectronsEquilibriumFamily suidaeFunctional disorderGenesGeneticGenus HippocampusHomeostasisHumanImmunohistochemistryIndustrial AccidentsInner mitochondrial membraneIntraperitoneal InjectionsInvestigationKnock-outLeigh DiseaseLinkLocomotionLongevityMetabolicMetabolismMitochondriaMitochondrial DiseasesModelingMonitorMotionMusMutateMutationNADHNADH oxidaseNeurologicNeurological outcomeNicotinamide MononucleotideOryctolagus cuniculusOxidation-ReductionOxygen ConsumptionPatientsPhenotypePoisoningProductionProtonsReactionRiskRoleSirtuinsSyndromeTechnologyTherapeuticTimeTissuesToxic effectZebrafishalternative treatmentcell injurycofactorcomplex IVconditioningdesigndisease phenotypedisease-causing mutationdrug developmenteffective therapyelectron donorexperimental studyglyoxylateimprovedimproved outcomeinhibitormetabolic poisonmitochondrial dysfunctionmouse modeloxidationpharmacologicpreventprotein complexrestorationsensorsmoke inhalation
项目摘要
PROJECT SUMMARY
The electron transport chain (ETC) in the inner mitochondrial membrane is essential for efficient ATP production
in the cell. ETC function can be disrupted both genetically and pharmacologically by mitochondrial diseases and
metabolic poisons, respectively. Inefficient ATP production affects all tissues, but particularly the brain with its
high energy demands, thus making this a deadly neurological problem. ETC dysfunction is often associated with
buildup of the initial electron donor, NADH, within the mitochondria. This increase in NADH corresponds with a
decrease in its oxidized form, NAD+, contributing to an overall NAD+/NADH ratio imbalance. Since NAD+ and
NADH are cofactors for many redox reactions in the cell, this results in redox imbalance and reduced metabolic
flux, intensifying the energy production problem.
Cyanide, a pharmacological ETC inhibitor, and Leigh syndrome, a collection of fatal genetic mitochondrial
diseases, both result in inefficient ATP production, NAD+/NADH ratio imbalances, and severe neurological
consequences. Few cyanide antidotes exist, all of which have a limited efficacious time window for
administration. No cure is available for any form of Leigh syndrome. We hypothesize that normalization of the
NAD+/NADH ratio will improve outcomes for both cyanide poisoning and Leigh syndrome. Within Aim 1 of this
proposal, we will investigate 1) if restoring NAD+/NADH ratio is sufficient for rescuing cyanide poisoning and 2)
what occurs downstream of restoring NAD+/NADH ratio in the context of cyanide poisoning. Within Aim 2, we
will determine if redox modulators can rescue disease phenotypes in an array of zebrafish models of Leigh
syndrome designed to cover a wide breadth of mutations associated with Leigh syndrome. These disease
phenotypes include glial reactivity and deficits in locomotion, oxygen consumption, and associative learning.
Collectively, these experiments will evaluate the therapeutic value of restoring the NAD+/NADH ratio for different
forms of mitochondrial dysfunction, and will focus on redox modulators that improve neurological outcomes.
项目摘要
线粒体内膜中的电子传递链(ETC)对于有效的ATP产生是必不可少的
得双曲余切值. ETC功能可以在遗传上和线粒体疾病中被破坏,
代谢毒素。ATP的生产效率低下会影响所有组织,尤其是大脑,
高能量需求,从而使其成为致命的神经系统问题。ETC功能障碍通常与
初始电子供体NADH在线粒体内的积累。NADH的这种增加对应于
其氧化形式NAD+减少,导致总体NAD+/NADH比率失衡。由于NAD+和
NADH是细胞中许多氧化还原反应的辅因子,这导致氧化还原失衡和代谢减少。
通量,加剧了能源生产问题。
氰化物,一种药理学ETC抑制剂,和Leigh综合征,一种致命的遗传线粒体疾病的集合
这两种疾病都导致ATP生产效率低下,NAD+/NADH比例失衡,以及严重的神经系统疾病。
后果几乎没有氰化物解毒剂存在,所有这些都具有有限的有效时间窗口,
局没有治愈任何形式的Leigh综合征。我们假设,正常化的
NAD+/NADH比值将改善氰化物中毒和Leigh综合征的结局。在目标1中,
建议,我们将调查1)恢复NAD+/NADH比率是否足以挽救氰化物中毒和2)
在氰化物中毒的情况下,恢复NAD+/NADH比率的下游发生了什么。在目标2中,我们
将确定氧化还原调节剂是否可以挽救一系列斑马鱼模型中的疾病表型
综合征,旨在涵盖与Leigh综合征相关的广泛突变。这些疾病
表型包括神经胶质反应性和运动、耗氧量和联合学习的缺陷。
总的来说,这些实验将评估对于不同的肿瘤恢复NAD+/NADH比率的治疗价值。
形式的线粒体功能障碍,并将重点放在氧化还原调节剂,改善神经系统的结果。
项目成果
期刊论文数量(0)
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Emily Tippetts的其他文献
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{{ truncateString('Emily Tippetts', 18)}}的其他基金
The role of redox balance in cyanide toxicity and mitochondrial disease
氧化还原平衡在氰化物毒性和线粒体疾病中的作用
- 批准号:
10536383 - 财政年份:2022
- 资助金额:
$ 3.73万 - 项目类别:
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