Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
基本信息
- 批准号:10116499
- 负责人:
- 金额:$ 34.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsAcetylcysteineAcuteAddressAffectAmino AcidsAntioxidantsAstrocytesBiological ModelsBrainBrain DiseasesChronicComplementCouplesCysteineCystineDataDendritic SpinesDiseaseDoseElectroencephalogramEpilepsyEquilibriumExhibitsExonsGlutamate ReceptorGlutamatesGlutathioneGlutathione DisulfideHigh Pressure Liquid ChromatographyHippocampus (Brain)HomeostasisImmunohistochemistryIndividualKainic AcidKnockout MiceKnowledgeLightMaintenanceMeasurementMediatingMolecularMorphologyMusMutationNeuraxisNeuronsNeurotransmittersOxidation-ReductionPentylenetetrazolePharmacologyPhenotypePhysiologicalProcessPumpRegulationRoleSignal TransductionSourceSpecificityStrokeSulfhydryl CompoundsSynapsesSystemTestingTimeTraumatic Brain InjuryVertebral columnWestern Blottingantiporterbrain electrical activitybrain tissueconditional knockoutdesignelectrical measurementexperimental studyextracellularin vivointerestnervous system disorderneuronal excitabilitynew therapeutic targetreceptorreceptor expressionresponsescale upsensor technologystemtherapeutic targettransmission process
项目摘要
PROJECT SUMMARY
In several brain disorders including epilepsy, stroke and traumatic brain injury, an imbalance between the
excitatory and inhibitory (E/I) neurotransmitter systems exists. Understanding fully the cellular and molecular
processes that underlie normal, physiological transmission is the first step in determining how aberrations of
such might be countered to provide such individuals with E/I imbalance symptomatic relief. Recent evidence
from our lab demonstrates a role for the cystine/glutamate antiporter System xc- (Sxc-) ─ which exports glutamate
and imports cystine, the latter of which is the rate-limiting substrate for the synthesis of the thiol antioxidant
glutathione ─ in maintenance of E/I balance. Specifically, we find that sut/sut mice, which harbor a natural
mutation in SLC7a11 (SLC7a11sut/sut) and are therefore devoid of Sxc-, are considerably more hyperexcitable
than their wild-type littermates upon acute challenge with kainic acid or pentylenetetrazole. Paradoxically, after
repeated sub-acute/sub-chronic administration of the same chemoconvulsants, SLC7a11sut/sut mice exhibit signs
of hypoexcitability, a response polar opposite to that which occurs in wild-type littermate controls. The idea that
these paradoxical findings may result from the same underlying mechanism ─ namely synaptic scaling ─ will be
explored in this proposal. State-of-the-art in vivo sensor technology, as well as, cellular, molecular and
pharmacological approaches will be used to test the hypothesis that chronic loss of Sxc- leads to a scaling up of
glutamate receptors under basal conditions, whereas scaling down occurs under conditions of enhanced
neuronal activity ─ both in efforts to stabilize neuronal firing. Whether these finding are mediated by changes in
glutamate and/or glutathione will also be explored. Studies to determine the cellular specificity of response, with
specific focus on the role of the astrocyte, are also planned. Overall, these studies are designed to increase our
mechanistic understanding of the contribution of astrocyte Sxc- to glutamate, glutathione and activity homeostasis
in in vivo brain. More broadly, these efforts complement other ongoing efforts to identify targets to treat the E/I
imbalance that exists in many neurological disorders.
项目摘要
在包括癫痫、中风和创伤性脑损伤在内的几种脑疾病中,
存在兴奋性和抑制性(E/I)神经递质系统。充分理解细胞和分子
正常生理传递的基础过程是确定
这可以被抵消以向这些个体提供E/I不平衡症状缓解。最近的证据
证明了胱氨酸/谷氨酸反向转运体系统xc-(Sxc-)的作用,该系统输出谷氨酸
并输入胱氨酸,后者是巯基抗氧化剂合成的限速底物
谷胱甘肽─维持E/I平衡。具体来说,我们发现,sut/sut小鼠,它们具有天然的
SLC 7a 11突变(SLC 7a 11 sut/sut),因此缺乏Sxc-,
在用红藻氨酸或戊四唑急性攻击时,巧合的是,
重复亚急性/亚慢性给予相同的化学惊厥剂,SLC 7a 11 sut/sut小鼠表现出体征
低兴奋性,与野生型同窝对照中发生的反应极性相反。的想法
这些自相矛盾的发现可能是由相同的潜在机制引起的,即突触缩放,
在这个提案中,最先进的体内传感器技术,以及细胞、分子和
药理学方法将被用来测试的假设,慢性损失的Sxc-导致规模扩大,
谷氨酸受体在基础条件下,而规模缩小发生在增强的条件下,
神经元活动─ ─两者都是为了稳定神经元放电。这些发现是否是由
谷氨酸和/或谷胱甘肽也将被探索。确定反应的细胞特异性的研究,
特别关注星形胶质细胞的作用,也计划。总的来说,这些研究旨在增加我们的
星形胶质细胞Sxc-对谷氨酸、谷胱甘肽和活性稳态贡献的机制理解
in vivo体内brain脑.更广泛地说,这些努力补充了其他正在进行的确定治疗E/I目标的努力。
这种失衡存在于许多神经系统疾病中。
项目成果
期刊论文数量(0)
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{{ truncateString('SANDRA J HEWETT', 18)}}的其他基金
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
- 批准号:
10214720 - 财政年份:2020
- 资助金额:
$ 34.91万 - 项目类别:
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
- 批准号:
10357770 - 财政年份:2018
- 资助金额:
$ 34.91万 - 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
- 批准号:
8302237 - 财政年份:2011
- 资助金额:
$ 34.91万 - 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
- 批准号:
8203292 - 财政年份:2011
- 资助金额:
$ 34.91万 - 项目类别:
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