Aging and Dementia: Cholinergic neuron biochemistry
衰老与痴呆:胆碱能神经元生物化学
基本信息
- 批准号:7567505
- 负责人:
- 金额:$ 33.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-03-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:AgingAlzheimer&aposs DiseaseAmyloid beta-ProteinBindingBiochemistryBrainCell Culture SystemCell DeathCellsCultured CellsDataDementiaDevelopmentEventFamilyGeneticLeadMapsMediatingMolecular ConformationMusMutationPathologyPhosphorylationPhosphotransferasesProcessProductionProtein ConformationProtein IsoformsProteinsReadingReceptor Protein-Tyrosine KinasesSerineSiteSystemTestingThreonineTissuesTumor Necrosis Factor-alphaTyrosine PhosphorylationWorkabeta depositionamyloid precursor protein processingcholinergic neurondesignhuman TNF proteinimmunocytochemistryneurofibrillary tangle formationnovel strategiesnovel therapeuticspresenilintau Proteinstau conformationtau interactiontau phosphorylationtau-1
项目摘要
DESCRIPTION (provided by applicant): This work is designed to build on our growing understanding of the mechanism by which tau becomes abnormal in Alzheimer's disease, and the critical factors that lead to tangle formation and cell death. We now seek to test new specific hypotheses regarding the mechanisms responsible for these events. Tyrosine phosphorylation of tau seems to be a very early event in AD, and the kinases responsible for these phosphorylations will be a major focus of this application. Mechanisms that can activate these kinases will also be examined to determine if associations with pathology can be demonstrated. New data on an apparent AD-specific phosphorylation of APP and the binding of Pin1 have suggested approaches to examination of the relationship between changes in APP processing and tau pathology. The specific aims are: 1. We will test the hypothesis that phosphorylation of tau on Y18 and/or 394 are candidates for production of conformational changes in tau in AD. Fyn and abl are the kinases that may be responsible for these phosphorylations, and the association of these proteins with tau pathology will be examined in detail. 2. The hypothesis that Abeta deposition triggers activation of src family kinases (and tyrosine phosphorylation of tau) has been proposed by others, and this will be tested in a rigorous fashion in the AD brain. The accumulation of pY18, fyn and abl with Abeta will be examined by immunocytochemistry using the same tissues employed in Aim 1. The possibility that Abeta effects on tyrosine phosphorylation of tau might be indirectly mediated through microglial production of TNF alpha will also be examined. 3. The interaction of tau with fyn and abl will be further examined in cultured cells. Cells will be transfected with specific tau isoforms along with fyn or abl. The hypothesis that tyrosine phosphorylation of tau causes conformational changes that may be sensitive to tau isoform composition will be tested. 4. We will test the hypothesis that changes in APP processing can induce changes in tau conformation and phosphorylation in cell culture systems selected to have a variety of tau isoform compositions. 5. Pin1 binds to both phosphorylated tau and phosphorylated APP, and both sites are phosphorylated in the AD brain. The hypothesis that Pin1 is involved in conformation changes of tau and perhaps in modifying APP processing will be tested. This work will help understand the process of AD, and help lead to new therapeutic strategies.
描述(申请人提供):这项工作旨在建立在我们对tau在阿尔茨海默病中变得异常的机制以及导致缠结形成和细胞死亡的关键因素的日益深入的理解的基础上。我们现在寻求测试有关这些事件的机制的新的具体假设。Tau的酪氨酸磷酸化在AD中似乎是一个非常早期的事件,负责这些磷酸化的激酶将是这一应用的主要焦点。可以激活这些激酶的机制也将被研究,以确定是否可以证明与病理的关联。关于APP明显的AD特异性磷酸化和Pin1结合的新数据表明,可以采用一些方法来研究APP处理过程的变化和tau病理之间的关系。具体目标是:1.我们将检验假设,即Y18和/或394上的tau磷酸化是导致AD中tau构象变化的候选因素。Fyn和ABL是可能导致这些磷酸化的激酶,这些蛋白与tau病理的关联将被详细研究。2.Abeta沉积触发src家族的激活(以及tau的酪氨酸磷酸化)的假说已经被提出,这一假说将在AD大脑中得到严格的验证。免疫细胞化学将检测pY18、Fyn和ABL与Abeta的结合情况。Abeta对tau酪氨酸磷酸化的影响可能是通过小胶质细胞产生的肿瘤坏死因子α间接介导的。3.在培养的细胞中,将进一步研究tau与Fyn和ABL的相互作用。细胞将与FYN或ABL一起被导入特定的tau亚型。Tau的酪氨酸磷酸化导致构象变化的假设将得到验证,这种变化可能对tau的异构体组成敏感。4.我们将检验这样一个假设,即APP加工的变化可以在选择具有不同tau亚型组成的细胞培养系统中引起tau构象和磷酸化的变化。5.Pin1与磷酸化的tau和磷酸化的APP结合,这两个位点在AD脑中都是磷酸化的。Pin1参与了tau的构象变化,可能还参与了APP的加工,这一假设将得到验证。这项工作将有助于理解AD的过程,并有助于指导新的治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
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PETER P DAVIES其他文献
PETER P DAVIES的其他文献
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{{ truncateString('PETER P DAVIES', 18)}}的其他基金
Aging and Dementia: Cholinergic neuron biochemistry
衰老与痴呆:胆碱能神经元生物化学
- 批准号:
7183517 - 财政年份:2006
- 资助金额:
$ 33.85万 - 项目类别:
Aging and Dementia: Cholinergic neuron biochemistry
衰老与痴呆:胆碱能神经元生物化学
- 批准号:
7037801 - 财政年份:2006
- 资助金额:
$ 33.85万 - 项目类别:
Aging and Dementia: Cholinergic neuron biochemistry
衰老与痴呆:胆碱能神经元生物化学
- 批准号:
7772363 - 财政年份:2006
- 资助金额:
$ 33.85万 - 项目类别:
Alterations in System Integrity Associated with Tauopathy Development
与 Tau 病发展相关的系统完整性的改变
- 批准号:
6966712 - 财政年份:2005
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD & Other Dementias
AD 中 Tau 蛋白病理学的小鼠模型
- 批准号:
7432316 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD & Other Dementias
AD 中 Tau 蛋白病理学的小鼠模型
- 批准号:
7586175 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD & Other Dementias
AD 中 Tau 蛋白病理学的小鼠模型
- 批准号:
7190038 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD & Other Dementias
AD 中 Tau 蛋白病理学的小鼠模型
- 批准号:
8055389 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD and Other Dementias
AD 和其他痴呆症中 Tau 蛋白病理学的小鼠模型
- 批准号:
8635108 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别:
A Mouse Model of Tau Pathology in AD and Other Dementias
AD 和其他痴呆症中 Tau 蛋白病理学的小鼠模型
- 批准号:
8850752 - 财政年份:2003
- 资助金额:
$ 33.85万 - 项目类别: