Glial Involvement in REDOX Homeostasis in the Substantia Nigra
胶质细胞参与黑质氧化还原稳态
基本信息
- 批准号:10805594
- 负责人:
- 金额:$ 55.71万
- 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 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAgeAgingAstrocytesAutopsyBehaviorBioinformaticsBiological AvailabilityBrainCellsCellular StressCharacteristicsDNA RepairDataDiseaseDopamineDown-RegulationEnzymesEquilibriumEtiologyEvaluationExhibitsExtracellular SpaceFunctional disorderGene ExpressionGenesGenetic TranscriptionGenetic VariationHealthHeterozygoteHomeostasisHumanImmuneImpairmentInflammationInflammatoryInheritedInjectionsKnockout MiceLaboratoriesLewy BodiesLewy neuritesLinkLipopolysaccharidesMaintenanceMediatorMessenger RNAMicrogliaMitochondriaModelingMotorMovement DisordersMusMutationNeurogliaNeurologicNeuronsNiacinamideNicotinamide adenine dinucleotideOntologyOxidative StressParkinson DiseasePathogenesisPathway interactionsPatientsPeripheralPhenotypeProcessProductionProteinsQuantitative Trait LociReactionRegulationResearch PersonnelRoleSingle Nucleotide PolymorphismSirtuinsSourceSubstantia nigra structureSynapsesTestingTissuesTranscriptVesicleWorkalpha synucleincarbohydrate metabolismcell typedisorder riskdopaminergic neuronexperimental studyextracellulargenome wide association studyimmune cell infiltrateinsightmRNA Expressionmitochondrial dysfunctionmouse modelneuron lossneuronal survivalneuropathologyneurotransmitter releasenicotinamide-beta-ribosidenovelpreventreconstitutionresponserisk variantsynaptic functionsynucleinopathytrafficking
项目摘要
PROJECT SUMMARY
Controversies exist regarding the contribution of glial cell dysregulation and inflammation to the pathogenesis
of Parkinson Disease (PD). Signs of inflammation have been detected in postmortem tissue of PD patients, and
recent evidence suggests that mutations in genes associated with familial PD can influence the function of
astrocytes and microglia. These findings, together with the existence of mutations in the HLA locus in PD
patients, have led investigators to propose an etiological role for inflammation and glial dysfunction in PD.
However, direct evidence is lacking for mechanistic links among inflammation, glial dysregulation, and the
neuronal loss characteristic of PD.
To identify potential cell-autonomous mediators of PD-relevant processes in glia, we used a bioinformatics
strategy to identify PD GWAS genes enriched in glial cells of the mouse brain. Interestingly, a small subset of
genes exhibits enrichment of expression in astrocytes. PD-linked single-nucleotide polymorphisms in one of
these genes, CD38, are associated with a ~45% reduction in CD38 transcript expression in the human brain.
Previous work has demonstrated a role for CD38 in peripheral immune cells, where it serves to regulate REDOX
balance in both intra- and extra-cellular compartments; the roles for CD38 in the brain have only recently been
explored. Preliminary experiments from our laboratory have shown that CD38 expression is enriched in
astrocytes of the human and mouse brain, NAD/NAM balance is disrupted in various regions of the CD38
knockout mouse brain, and inflammation and CD38 deficiency synergistically interact to influence motor function.
Here, we propose to use CD38 as a prototypical gene to understand ways in which glial dysfunction can give
rise to a PD-like phenotype in mice by investigating 1) the requirement for CD38 in the maintenance of REDOX
homeostasis and dopaminergic neuron function and viability in aging mice, 2) the role for CD38 in the regulation
of inflammation in the substantia nigra, and 3) the impact of CD38 modulation on the vulnerability of dopaminergic
neurons in two synucleinopathy mouse models of PD. A subset of experiments will test the involvement of
REDOX dysregulation in the changes observed in CD38-deficient mice by determining whether provision of
nicotinamide riboside, a bioavailable NAD precursor, can prevent dopaminergic oxidative stress, cell dysfunction,
and loss. Altogether, these experiments have the potential to reveal mechanistic contributors to increased
neuronal vulnerability with glial dysfunction and provide novel information about the roles for glia in maintaining
dopaminergic neuron survival in aging and disease.
项目摘要
关于胶质细胞失调和炎症在发病机制中的作用存在争议
帕金森病(PD)在PD患者的死后组织中检测到炎症迹象,
最近的证据表明,与家族性PD相关的基因突变可以影响PD的功能,
星形胶质细胞和小胶质细胞。这些发现,加上PD患者HLA基因座突变的存在,
患者,导致研究人员提出炎症和神经胶质功能障碍在PD中的病因作用。
然而,炎症、胶质细胞失调和神经胶质细胞增殖之间的机制联系缺乏直接证据。
PD的神经元损失特征。
为了鉴定胶质细胞中PD相关过程的潜在细胞自主介质,我们使用生物信息学方法,
这是一种鉴定小鼠脑神经胶质细胞中富集的PD GWAS基因的策略。有趣的是,
基因在星形胶质细胞中表现出表达富集。PD连锁的单核苷酸多态性,
这些基因,CD 38,与人脑中CD 38转录本表达的~45%减少有关。
以前的工作已经证明了CD 38在外周免疫细胞中的作用,在那里它可以调节REDOX
在细胞内和细胞外室的平衡; CD 38在大脑中的作用只是最近才被发现。
探讨了我们实验室的初步实验表明,CD 38的表达是富集的,
在人和小鼠脑的星形胶质细胞中,NAD/NAM平衡在CD 38的各个区域被破坏,
敲除小鼠脑,炎症和CD 38缺陷协同相互作用影响运动功能。
在这里,我们建议使用CD 38作为一个原型基因,以了解神经胶质功能障碍的方式可以给
通过研究1)在维持REDOX中对CD 38的需求,
稳态和多巴胺能神经元的功能和活力,2)CD 38在调节中的作用
黑质炎症的影响,以及3)CD 38调节对多巴胺能神经元脆弱性的影响。
两种突触核蛋白病小鼠PD模型中的神经元。一组实验将测试
通过确定是否提供CD 38-缺陷小鼠中观察到的变化中的REDOX失调,
烟酰胺核苷,一种生物可利用的NAD前体,可以预防多巴胺能氧化应激,细胞功能障碍,
和失去总而言之,这些实验有可能揭示增加的机械贡献者。
神经元的脆弱性与神经胶质功能障碍,并提供新的信息,神经胶质细胞在维持
多巴胺能神经元在衰老和疾病中的存活。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Rita Marie Cowell其他文献
Rita Marie Cowell的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Rita Marie Cowell', 18)}}的其他基金
Cell-type-specific contributions to cortical dysfunction in frontotemporal dementia
细胞类型特异性对额颞叶痴呆皮质功能障碍的影响
- 批准号:
10317335 - 财政年份:2021
- 资助金额:
$ 55.71万 - 项目类别:
Cell-type-specific contributions to cortical dysfunction in frontotemporal dementia
细胞类型特异性对额颞叶痴呆皮质功能障碍的影响
- 批准号:
10758410 - 财政年份:2021
- 资助金额:
$ 55.71万 - 项目类别:
Glial Involvement in REDOX Homeostasis in the Substantia Nigra
胶质细胞参与黑质氧化还原稳态
- 批准号:
10307017 - 财政年份:2021
- 资助金额:
$ 55.71万 - 项目类别:
Glial Involvement in REDOX Homeostasis in the Substantia Nigra
胶质细胞参与黑质氧化还原稳态
- 批准号:
10426369 - 财政年份:2021
- 资助金额:
$ 55.71万 - 项目类别:
The Nigral Molecular Clock and Vulnerability to Neurodegeneration
黑质分子钟和神经退行性疾病的脆弱性
- 批准号:
10383744 - 财政年份:2018
- 资助金额:
$ 55.71万 - 项目类别:
Transcriptional regulation of metabolism in neurons
神经元代谢的转录调控
- 批准号:
9468448 - 财政年份:2017
- 资助金额:
$ 55.71万 - 项目类别:
Transcriptional regulation of metabolism in neurons
神经元代谢的转录调控
- 批准号:
9332719 - 财政年份:2017
- 资助金额:
$ 55.71万 - 项目类别:
Transcriptional regulation of metabolism in neurons
神经元代谢的转录调控
- 批准号:
10133160 - 财政年份:2017
- 资助金额:
$ 55.71万 - 项目类别:
Transcriptional regulation of metabolism in neurons
神经元代谢的转录调控
- 批准号:
9898487 - 财政年份:2017
- 资助金额:
$ 55.71万 - 项目类别:
PGC-1alpha and GABAergic Dysfunction in Huntington Disease
亨廷顿病中的 PGC-1α 和 GABA 能障碍
- 批准号:
8247783 - 财政年份:2010
- 资助金额:
$ 55.71万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation
根据造血干细胞移植后甲基化年龄估算干细胞衰老现象
- 批准号:
23K07844 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of Age-dependent Functional Changes in Skeletal Muscle CB1 Receptors by an in Vitro Model of Aging-related Muscle Atrophy
通过衰老相关性肌肉萎缩的体外模型分析骨骼肌 CB1 受体的年龄依赖性功能变化
- 批准号:
22KJ2960 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Joint U.S.-Japan Measures for Aging and Dementia Derived from the Prevention of Age-Related and Noise-induced Hearing Loss
美日针对预防与年龄相关和噪声引起的听力损失而导致的老龄化和痴呆症联合措施
- 批准号:
23KK0156 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Fund for the Promotion of Joint International Research (International Collaborative Research)
The Effects of Muscle Fatigability on Gait Instability in Aging and Age-Related Falls Risk
肌肉疲劳对衰老步态不稳定性和年龄相关跌倒风险的影响
- 批准号:
10677409 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Characterizing gut physiology by age, frailty, and sex: assessing the role of the aging gut in "inflamm-aging"
按年龄、虚弱和性别表征肠道生理学特征:评估衰老肠道在“炎症衰老”中的作用
- 批准号:
497927 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
- 批准号:
10679287 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Role of AGE/RAGEsignaling as a driver of pathological aging in the brain
AGE/RAGE信号传导作为大脑病理性衰老驱动因素的作用
- 批准号:
10836835 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Elucidation of the protein kinase NLK-mediated aging mechanisms and treatment of age-related diseases
阐明蛋白激酶NLK介导的衰老机制及年龄相关疾病的治疗
- 批准号:
23K06378 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Underlying mechanisms of age-related changes in ingestive behaviors: From the perspective of the aging brain and deterioration of the gustatory system.
与年龄相关的摄入行为变化的潜在机制:从大脑老化和味觉系统退化的角度来看。
- 批准号:
23K10845 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Targeting Age-Activated Proinflammatory Chemokine Signaling by CCL2/11 to Enhance Skeletal Muscle Regeneration in Aging
通过 CCL2/11 靶向年龄激活的促炎趋化因子信号传导以增强衰老过程中的骨骼肌再生
- 批准号:
478877 - 财政年份:2023
- 资助金额:
$ 55.71万 - 项目类别:
Operating Grants