mitoNEET as a therapeutic target for mitigating ischemic brain injury following MCAO
mitoNEET as a therapeutic target for mitigating ischemic brain injury following MCAO
批准号:
10735923
负责人:
Werner Geldenhuys
金额:
$54.95万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2028-07-31
关键词:
AcuteAddressAdvanced DevelopmentApoproteinsApoptosisAreaAttenuatedBasic ScienceBioenergeticsBlood - brain barrier anatomyBlood brain barrier dysfunctionBrainBrain InjuriesCardiovascular systemCause of DeathCell RespirationCellsCellular StressClinical ResearchCommunicationConsumptionDataDisabled PersonsDiseaseEndothelial CellsFemaleFoundationsGenerationsGlucoseGoalsHealthIn VitroInfarctionIronIschemiaIschemic Brain InjuryIschemic StrokeKnowledgeLibrariesLigandsLinkLipid PeroxidationLiteratureMediatingMedicalMetabolicMiddle Cerebral Artery OcclusionMissionMitochondriaMitochondrial ProteinsModelingMusNational Institute of Neurological Disorders and StrokeNervous System TraumaNeurologicNeuronsOncogenicOuter Mitochondrial MembraneOxidation-ReductionOxidative StressOxygenParentsPathway interactionsPhasePioglitazonePlayPre-Clinical ModelProteinsPublic HealthRattusReactive Oxygen SpeciesReperfusion InjuryReperfusion TherapyResearchRiskRodentRoleSeveritiesSpecificityStrokeSulfurTestingTherapeuticTherapeutic EffectTherapeutic InterventionTissuesUnited States National Institutes of HealthWorkagedblood-brain barrier disruptionblood-brain barrier functionblood-brain barrier permeabilizationbrain endothelial cellbrain tissuecell injurycerebral microvasculaturedeprivationdesigndisabilitydrug discoveryfunctional disabilityfunctional improvementimprovedimproved outcomein vitro Modelinjuredinnovationinsightinterestmalemitochondrial dysfunctionnervous system disorderneuroinflammationneuron lossneuronal survivalneuropathologyneuroprotectionnew therapeutic targetnovelnovel therapeuticspost strokepre-clinicalpreclinical studyrepairedresponsesensorstressorstroke outcomestroke recoverytargeted treatmenttemporal measurementtherapeutic targettool
中文摘要
项目总结
越来越多的证据表明,缺血性中风后低血流灌注的脑组织功能障碍
由于氧化作用显著减少,半暗带神经元之间的电通讯受到干扰
新陈代谢。因此,很明显,线粒体功能障碍在神经细胞的程度中起着中心作用。
缺血性脑损伤后死亡;然而,线粒体迟迟不能完全
调查过了。通过偶然发现吡格列酮的非靶向治疗作用,一种小的
线粒体铁硫簇蛋白(mitoNEET,MNT)被发现,在治疗方面重新引起了人们的兴趣
线粒体为靶点。MitoNEet嵌入线粒体膜外膜,作为氧化还原和
PH传感器调节线粒体生物能量学,特别是对细胞应激的反应。使用吡格列酮
作为母体化合物,我们设计了一种对锰具有高度特异性的一级配体NL-1。使用NL-1,我们
在中风的神经病理和功能障碍方面有显著的改善
小鼠和大鼠一过性大脑中动脉闭塞(MCAO)模型。这项提议的目标是解决
关于MNT如何在脑内发挥作用以缓解急性脑缺血的基本知识空白
受伤。我们的中心假设是,MNT的调节作用于改善脑内脆弱的神经元。
通过减少过量铁诱导的脂质过氧化和神经元增加的恶性循环来实现半暗带
死亡。基于大量以前的文献和试验数据,我们假定NL-1的初始活动目标
是大脑的微血管系统;因此,我们提出了两个特定的目标来检验我们的假设。在具体目标1中,
我们将使用4细胞Transwell体外血液模型来测试MNT选择性配体NL-1是否缓解铁下垂。
缺氧缺糖再灌流后的脑屏障。然而,在具体的目标2中,我们将测试
MNT配体NL-1可减少MCAO后脑铁蓄积和血脑屏障功能障碍。成功
拟议研究的完成预计将提供:(1)更好地了解MNT如何以及在哪里
减轻缺血性中风后的脑损伤;(2)对线粒体功能障碍的影响的新见解
生物能量学对缺血性卒中预后的影响;&(3)介入治疗的坚实科学基础
治疗缺血性卒中的治疗方法。通过这些方法获得的机制和临床前数据
这些研究将成为推进线粒体靶向疗法发展的关键里程碑
治疗神经损伤和疾病。
英文摘要
PROJECT SUMMARY
Accumulating evidence suggests that following ischemic stroke hypoperfused brain tissue is functionally disabled
as electrical communication among penumbral neurons is disrupted due to marked reductions in oxidative
metabolism. Thus, it is apparent that mitochondrial dysfunction plays a central role in the degree of neuronal cell
death encountered following ischemic brain injury; however, mitochondria have been slow to be fully
investigated. Through a serendipitous discovery of an off-target therapeutic effect of pioglitazone, a small
mitochondrial iron-sulfur cluster protein, mitoNEET (mNT) was identified that has renewed interest in therapeutic
targeting of mitochondria. MitoNEET is embedded in the outer mitochondrial membrane and acts as a redox and
pH sensor to regulate mitochondrial bioenergetics, especially in response to cellular stress. Using pioglitazone
as our parent compound, we designed NL-1, a first-in-class ligand with high specificity for mN. Using NL-1, we
have demonstrated marked improvements in stroke neuropathology and functional impairment following
transient middle cerebral artery occlusion (MCAO) in mice and rats. The objective of this proposal is to address
fundamental gaps in knowledge regarding how mNT works within the brain to mitigate acute ischemic brain
injury. Our central hypothesis is that modulation of mNT acts to improve vulnerable neurons within the
penumbra by reducing the vicious cycle of excessive iron-induced lipid peroxidation and increased neuronal
death. Based on a strong body of prior literature and pilot data, we postulate the initial target of activity for NL-1
is the cerebral microvasculature; thus, we propose two specific aims to test our hypothesis. In specific aim 1,
we will test if mNT selective ligand, NL-1, mitigates ferroptosis using a 4 cell Transwell in vitro model of the blood-
brain barrier following oxygen-glucose deprivation with reperfusion. Whereas, in specific aim 2, we will test if
mNT ligand, NL-1, reduces brain iron accumulation and blood-brain barrier dysfunction post-MCAO. Successful
completion of the proposed research is expected to provide a: (1) greater understanding of how & where mNT
mitigates brain injury following ischemic stroke; (2) new insight into the impact of mitochondrial dysfunction &
diminished bioenergetics on ischemic stroke outcomes; & (3) strong scientific foundation for an interventional
therapeutic approach for treating ischemic stroke. The mechanistic & preclinical data obtained through these
studies will serve as critical milestones for advancing the development of mitochondria-targeted therapies for
treating neurological injuries & disease.
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批准号:10693638
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项目类别:
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资助金额:$34.49万
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财政年份:2023
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负责人:Werner Geldenhuys
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依托单位:
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项目类别:
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财政年份:2014
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负责人:Werner Geldenhuys
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依托单位:
Targeting the mitochondrial protein mitoNEET for the treatment of reperfusion-injury after stroke
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批准号:10025932
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项目类别:
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资助金额:$26.6万
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财政年份:2014
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负责人:Werner Geldenhuys
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依托单位:
海外基金