Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
基本信息
- 批准号:9757818
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAffectiveAgeAnimalsAstrocytesBehavioralBrainBreedingCAG repeatCellsCessation of lifeClinicalCognitiveCorpus striatum structureDataDiseaseDominant-Negative MutationElectrophysiology (science)ExocytosisExtracellular SpaceGenesGeneticGlial Fibrillary Acidic ProteinGlutamate ReceptorGlutamate TransporterGlutamatesGoalsHigh Pressure Liquid ChromatographyHuntington DiseaseHuntington geneHuntington proteinKnowledgeLaboratoriesLeadLengthMeasuresMechanical StimulationMicrodialysisMotorMusMutateN-Methyl-D-Aspartate ReceptorsNatureNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsOnset of illnessPathogenesisPatientsPhenotypePhysiologyPlayRiskRoleSNAP receptorSiteSliceSourceSymptomsSynapsesSynaptic TransmissionTestingTherapeutic InterventionToxic effectbasecell typeclinical Diagnosisdesigndisabilitydisease phenotypeeffective therapyexcitotoxicityextracellularin vivomotor deficitmouse modelmutantnervous system developmentneuronal excitabilityneurotransmissionnovel therapeutic interventionpublic health relevancetransmission processvesicular releasevoltage clamp
项目摘要
DESCRIPTION (provided by applicant): Huntington's disease (HD) is an adult-onset autosomal dominant neurodegenerative disorder characterized clinically by cognitive, psychiatric and motor deficits which progress to severe disability and death. To date there are no affective treatments for HD. The mutated huntingtin (mHTT) protein is widely expressed in neuronal and non-neuronal cells, yet neurodegeneration critically affects a few subsets of neuronal cell types in the brain. Understanding the toxicity produced by mhtt in non-neuronal cell types and the basis for this selective neurodegeneration are likely to be critical in the desin of effective therapies for the disease. The goal of this proposal is to expand our knowledge of the contribution of full length-mHTT (fl-mHTT) expressing astrocytes to neurodegeneration in HD. Astrocytes are critical to the proper function and development of the nervous system. They are involved in modulating synaptic activity and neurotransmission. Studies from our laboratory have uncovered increased SNARE-dependent glutamate release from astrocytes in culture taken from the conditional fl-mHTT expressing BACHD mouse model. This is a new found disruption caused by fl-mHTT expression in the astrocytes, which further implicates these cells in HD pathogenesis. Furthermore, we demonstrate that reducing fl-mHTT expression in astrocytes in vivo, contributes to the behavioral and neuropathological phenotypes observed in the conditional BACHD mouse model. The studies proposed here will further our understanding of astrocyte contribution to HD and determine if targeting this cell type for therapeutic intervention is worthwhile. We will use conditional genetic mouse models in these studies and propose three aims: 1) To determine if fl-mHTT expressing astrocytes contribute to HD pathogenesis by increasing glutamate levels in BACHD mice through exocytosis of glutamate; 2) To determine if expression of mutant huntingtin in astrocytes contributes to the abnormal medium spiny neuron physiology observed in BACHD mice; and 3) To determine if decreasing fl-mHTT expression in astrocytes after disease onset in BACHD mice is sufficient to alleviate HD symptoms and whether astrocyte specific expression in a new mouse model is sufficient to cause HD-like phenotypes in mice. Together these studies will help to define the role of fl-mHTT within astrocytes in HD pathogenesis, and may lead to novel therapeutic approaches for treatment of HD.
描述(申请人提供):亨廷顿病(HD)是一种成人起病的常染色体显性神经退行性疾病,临床特征是认知、精神和运动障碍,进展为严重残疾和死亡。到目前为止,还没有针对HD的有效治疗方法。突变的亨廷顿蛋白(MHTT)在神经细胞和非神经细胞中广泛表达,但神经退行性变严重影响大脑中几种神经细胞类型。了解mHTT在非神经细胞类型中产生的毒性以及这种选择性神经变性的基础可能对于设计有效的疾病治疗方法至关重要。这项建议的目的是扩大我们对全长mHTT(FL-mHTT)表达的星形胶质细胞在HD神经变性中的作用的认识。星形胶质细胞对神经系统的正常功能和发育至关重要。它们参与调节突触活动和神经传递。我们实验室的研究发现,在表达BACHD小鼠模型的条件性fl-mHTT培养中,星形胶质细胞释放的谷氨酸依赖于圈套。这是一个新发现的由星形胶质细胞中fl-mHTT表达引起的干扰,进一步表明这些细胞参与了HD的发病机制。此外,我们还证明,在体内减少星形胶质细胞中fl-mHTT的表达有助于在条件性BACHD小鼠模型中观察到行为和神经病理表型。这里提出的研究将进一步加深我们对星形胶质细胞在HD中的作用的理解,并确定针对这种细胞类型进行治疗干预是否值得。我们将在这些研究中使用条件遗传学小鼠模型,并提出三个目标:1)确定表达fl-mHTT的星形胶质细胞是否通过谷氨酸排泄增加BACHD小鼠的谷氨酸水平,从而促进HD的发病;2)确定突变的Huntingtin在星形胶质细胞中的表达是否与BACHD小鼠中观察到的异常中等刺神经元生理学有关;3)确定BACHD小鼠发病后减少星形胶质细胞中fl-mHTT的表达是否足以缓解HD症状,以及在新的小鼠模型中,星形胶质细胞的特异性表达是否足以导致小鼠出现HD样表型。总之,这些研究将有助于确定星形胶质细胞中fl-mHTT在HD发病机制中的作用,并可能导致HD治疗的新的治疗方法。
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)
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Michelle Gray其他文献
Michelle Gray的其他文献
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{{ truncateString('Michelle Gray', 18)}}的其他基金
Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
- 批准号:
10231078 - 财政年份:2015
- 资助金额:
$ 38.75万 - 项目类别:
Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
- 批准号:
10437708 - 财政年份:2015
- 资助金额:
$ 38.75万 - 项目类别:
Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
- 批准号:
10663211 - 财政年份:2015
- 资助金额:
$ 38.75万 - 项目类别:
Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
- 批准号:
10840162 - 财政年份:2015
- 资助金额:
$ 38.75万 - 项目类别:
Exploring the contribution of astrocytes to Huntington disease
探索星形胶质细胞对亨廷顿病的贡献
- 批准号:
9324375 - 财政年份:2015
- 资助金额:
$ 38.75万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8456153 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
7871941 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8642674 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
The Role of Astrocytes in Huntington's Disease
星形胶质细胞在亨廷顿病中的作用
- 批准号:
8247166 - 财政年份:2010
- 资助金额:
$ 38.75万 - 项目类别:
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