Cerebral Microvascular Bioenergetics and Neurovascular Coupling
脑微血管生物能学和神经血管耦合
基本信息
- 批准号:10341164
- 负责人:
- 金额:$ 50.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AcuteAnimalsAntidiabetic DrugsBioenergeticsBiologyBlood GlucoseBlood VesselsBlood capillariesBrainC57BL/6 MouseCaliberCardiovascular systemCellsCerebrovascular CirculationCerebrovascular DisordersCerebrumClinicalCognitiveComplications of Diabetes MellitusCoupledDangerousnessDataDementiaDiabetes MellitusDiscriminationElectron Spin Resonance SpectroscopyEndothelial CellsEndotheliumGenerationsGenus HippocampusHypoglycemiaImpaired cognitionImpairmentInjuryInsulinInsulin-Dependent Diabetes MellitusKnock-outKnockout MiceLaser Scanning MicroscopyLeptin receptor mutationLinkMeasuresMediatingMeta-AnalysisMethodsMicrovascular DysfunctionMitochondriaModelingMorbidity - disease rateMusNOS1 geneNeuronsNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type INon-Insulin-Dependent Diabetes MellitusOxidative StressOxygen ConsumptionPatientsPeripheralPhysiologicalPlayProductionProtein IsoformsReactive Oxygen SpeciesRecurrenceRegulationResearchRespirationRiskRoleSalineSomatosensory CortexStreptozocinSymptomsTestingTextureTherapeuticTimeVariantVibrissaeWorkawakeblood glucose regulationbrain dysfunctionbrain endothelial cellcardiovascular disorder riskcerebral microvasculaturecerebrovascularcognitive functiondb/db mousedementia riskdiabetic patientexperienceextracellularhypoglycemia unawarenessin vivomitochondrial dysfunctionmortalityneglectneurovascular couplingnovelresponsesensorside effecttwo-photon
项目摘要
Summary
Brain microvessels play an important role in the neurovascular coupling (NVC). Mitochondria are energy sensors
of cells. My work for the first time demonstrated the link between mitochondrial depolarization and activation of
nitric oxide synthases (NOS). Recently, we have made a novel discovery of a neuronal NOS (nNOS) isoform in
endothelial cells that uniquely produce reactive oxygen species (ROS). The nNOS is co-expressed with NO-
producing eNOS in endothelial cells and both isoforms are involved in the bidirectional regulation of
mitochondria. Diabetes mellitus (DM) increases the risk of cerebrovascular dysfunction and dementia.
Importantly, hypoglycemia is a dangerous side effect of DM treatments, particularly insulin-therapy. Patients with
DM often experience mild hypoglycemia, but these episodes are unaccounted for in determining the
cardiovascular morbidity and mortality. We achieved a technological breakthrough utilizing Seahorse XFe24
analyzer and determined the mitochondrial respiration and cellular bioenergetics of brain microvessels. We made
a novel observation that five episodes of recurrent hypoglycemia (RH) impaired the microvascular mitochondrial
function. Notably, single episode of acute mild or severe hypoglycemia as well as Impairments of NOS activity
was found to mediate RH-induced alterations of cellular bioenergetics. Thus, we hypothesize that mild RH
disrupts NVC by promoting microvascular mitochondrial dysfunction leading to impaired cognitive function. We
further hypothesize that increased nNOS-induced oxidative stress coupled with reduced eNOS-derived NO
contribute to the mitochondrial dysfunction following RH. We propose to use streptozotocin treated C57Bl/6 mice
and db/db mice with leptin receptor mutation as models of diabetes with untreated mice as controls. In addition,
we will employ eNOS knockout and inducible endothelial cell specific nNOS knockout mice to investigate the
role of NOS isoforms in RH-induced microvascular dysfunction. Each animal will be subjected to five episodes
(one per day) of mild (blood glucose 70-80 mg/dl) or severe (blood glucose 40-54 mg/dl) insulin-induced
hypoglycemia or saline control. Aim 1 is to demonstrate that mild and severe RH (in vivo) can increase the
production of NOS-derived ROS and display RH-induced functional mitochondrial respiration deficits in cerebral
microvessels (ex vivo). Aim 2 is to establish the impact of RH on NVC in vivo. We will determine the RH-induced
deficits in NVC by measuring the changes in arteriolar and capillary diameter in response to neuronal activation
(whisker stimulation) in awake mice using two-photon laser scanning microscopy. Aim 3 is to determine the
impact of RH on cognitive function using novel texture discrimination task and modified Y-maze test. The results
of this proposal would identify the mechanistic link between mild RH and the cerebral microvascular mitochondria
dysfunction and challenge the existing dogma to demonstrate that mild RH is equally detrimental as severe RH
in contributing to the DM-induced cerebrovascular dysfunction, impaired NV, and cognitive dysfunction.
概括
脑微血管在神经血管耦合(NVC)中起重要作用。线粒体是能量传感器
细胞。我的工作首次证明了线粒体去极化与激活之间的联系
一氧化氮合酶(NOS)。最近,我们在新发现的发现中发现了神经元NOS(NNOS)的同工型
独特产生活性氧(ROS)的内皮细胞。 NNOS与NO-共表达
在内皮细胞中产生eNOS,两种同工型都参与了双向调节
线粒体。糖尿病(DM)增加了脑血管功能障碍和痴呆症的风险。
重要的是,低血糖是DM治疗的危险副作用,尤其是胰岛素治疗。患者
DM通常患有轻度低血糖症,但这些发作在确定
心血管发病率和死亡率。我们利用Seahorse XFE24取得了技术突破
分析仪并确定了脑微血管的线粒体呼吸和细胞生物能学。我们做了
一个新的观察结果,即五个复发性低血糖(RH)损害了微血管线粒体
功能。值得注意的是,急性轻度或严重低血糖症的单个发作以及NOS活性的障碍
发现可以介导RH诱导的细胞生物能量改变。因此,我们假设温和的RH
通过促进微血管线粒体功能障碍来破坏NVC,从而导致认知功能受损。我们
进一步假设,增加了NNOS诱导的氧化应激以及递减的eNOS衍生的NO
RH后有助于线粒体功能障碍。我们建议使用经治疗的C57BL/6小鼠的链霉菌素
用瘦素受体突变作为具有未处理小鼠的糖尿病模型的DB/DB小鼠作为对照。此外,
我们将采用eNOS敲除和可诱导的内皮细胞特异性nnos敲除小鼠进行研究
NOS同工型在RH诱导的微血管功能障碍中的作用。每只动物将受到五集
(每天一份)轻度(血糖70-80 mg/dl)或严重(血糖40-54 mg/dl)胰岛素诱导的
低血糖或盐水控制。目的1是证明轻度和严重的RH(体内)可以增加
在大脑中产生NOS衍生的ROS和显示RH诱导的功能性线粒体呼吸缺陷
微血管(Ex Vivo)。目标2是建立RH对NVC在体内的影响。我们将确定RH诱导的
通过测量对神经元激活的小动脉和毛细管直径的变化,NVC缺陷
(晶须刺激)使用两光子激光扫描显微镜在清醒小鼠中。目标3是确定
使用新型纹理歧视任务和修改的Y迷宫测试对RH对认知功能的影响。结果
该提案将确定轻度RH与脑微血管线粒体之间的机械联系
功能障碍并挑战现有教条,以证明温和的RH同样有害于严重的RH
在导致DM引起的脑血管功能障碍,NV受损和认知功能障碍时。
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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Prasad V Katakam其他文献
Prasad V Katakam的其他文献
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{{ truncateString('Prasad V Katakam', 18)}}的其他基金
Peroxynitrite is a Molecular Determinant of Impaired Microvascular Energetics in Alzheimer's Disease
过氧亚硝酸盐是阿尔茨海默氏病微血管能量受损的分子决定因素
- 批准号:
10631129 - 财政年份:2021
- 资助金额:
$ 50.86万 - 项目类别:
Peroxynitrite is a Molecular Determinant of Impaired Microvascular Energetics in Alzheimer's Disease
过氧亚硝酸盐是阿尔茨海默氏病微血管能量受损的分子决定因素
- 批准号:
10307476 - 财政年份:2021
- 资助金额:
$ 50.86万 - 项目类别:
Cerebral Microvascular Bioenergetics and Neurovascular Coupling
脑微血管生物能学和神经血管耦合
- 批准号:
10152682 - 财政年份:2020
- 资助金额:
$ 50.86万 - 项目类别:
Cerebral Microvascular Bioenergetics and Neurovascular Coupling
脑微血管生物能学和神经血管耦合
- 批准号:
10052940 - 财政年份:2020
- 资助金额:
$ 50.86万 - 项目类别:
Cerebral Microvascular Bioenergetics and Neurovascular Coupling
脑微血管生物能学和神经血管耦合
- 批准号:
10579198 - 财政年份:2020
- 资助金额:
$ 50.86万 - 项目类别:
Endothelial Expression of Neuronal Nitric Oxide Synthase
神经元一氧化氮合酶的内皮表达
- 批准号:
9305167 - 财政年份:2016
- 资助金额:
$ 50.86万 - 项目类别:
Endothelial Expression of Neuronal Nitric Oxide Synthase
神经元一氧化氮合酶的内皮表达
- 批准号:
9124378 - 财政年份:2016
- 资助金额:
$ 50.86万 - 项目类别:
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