Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
基本信息
- 批准号:8286953
- 负责人:
- 金额:$ 0.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-08-01 至 2012-07-03
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinity ChromatographyAlzheimer disease preventionAlzheimer&aposs DiseaseAmyloid beta-Protein PrecursorBindingBrainCellsCognitiveDementiaDepositionDeteriorationDevelopmentDiagnosisDiseaseEventGenerationsGenetic RecombinationGlycogen Synthase Kinase 3Glycogen Synthase KinasesGoalsGrantHealthInterventionInvestigationKRP proteinKnock-outKnockout MiceKnowledgeLaboratory StudyLeadLinkMediatingMediator of activation proteinMedicalMolecularMusNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathogenesisPathologyPhosphotransferasesPhysiologicalPlayPreventionProcessProductionProtein IsoformsProteinsRegulationRoleSenile PlaquesSeriesStructureSymptomsTestingTransgenic MiceUnited Statesamyloid peptidebasedefined contributiondesignhyperphosphorylated tauin vivoinhibitor/antagonistmouse modelneurofibrillary tangle formationnew therapeutic targetnoveloverexpressionpreventprotein aggregateprotein transportresearch studyskillstau Proteinstau phosphorylationtherapeutic development
项目摘要
Alzheimer's disease (AD) is a neurodegenerative disease characterized by a deterioration of cognitive skills,
eventually progressing to dementia. AD pathology is believed to result from an accumulation of insoluble
amyloid plaques and neurofibrillary tangles. Recent studies have demonstrated a role for two highly related
protein kinases, glycogen synthase kinase-3¿ and ¿ (GSK-3¿ and GSK-3¿), in the regulation of ¿-amyloid
peptide production. These molecules have previously been directly implicated in neurofibrillary tangle
formation, suggesting that GSK-3 isoforms are important mediators of AD pathology. Our long-term goal is to
better understand how GSK-3 activity contributes to the pathogenesis of AD. As a step toward attaining this
long-term goal, we have created mice that will allow for the conditional knockout of both GSK-3¿ and GSK-3¿.
The specific hypothesis we wish to test is that inactivation of GSK-3¿ decreases ¿-amyloid peptide production
and prevents the onset of AD pathology. These mice, and the cells derived from these mice, will permit us to
begin addressing the molecular basis of how GSK-3 activity contributes to AD pathogenesis and
neurodegeneration.
Specific Aim 1: Define the contribution of each GSK-3 isoform toward the events leading to the pathogenesis of
Alzheimer's disease.
Specific Aim 2: Delineate the molecular basis of the differential effects of GSK-3¿ and GSK-3¿ on the
production of ¿-amyloid peptides.
Specific Aim 3: Examine the effects of conditionally deleting GSK-3¿ and GSK-3¿ on the pathogenesis of
Alzheimer's disease.
The aims proposed above utilize our novel GSK-3 conditional knockout mice, thus affording us an opportunity
to make significant strides toward understanding the molecular mechanism by which GSK-3 isoforms
participate in Alzheimer's disease. This application proposes experiments designed to gain a better understanding of how Alzheimer's disease
develops. It is our hope that this increased knowledge will lead to the development of therapeutics capable of
slowing or preventing the symptoms associated with Alzheimer's disease.
阿尔茨海默病(AD)是一种神经退行性疾病,其特征是认知能力下降,
最终进展为痴呆症。 AD 病理学被认为是由不溶性物质的积累造成的
淀粉样蛋白斑和神经原纤维缠结。最近的研究证明了两种高度相关的作用
蛋白激酶、糖原合酶激酶-3¿ 和 ¿(GSK-3¿ 和 GSK-3¿),在 ¿-淀粉样蛋白的调节中
肽生产。这些分子先前已被直接涉及神经原纤维缠结
形成,表明 GSK-3 亚型是 AD 病理学的重要介质。我们的长期目标是
更好地了解 GSK-3 活性如何促进 AD 的发病机制。作为实现这一目标的一步
为了实现长期目标,我们创造了能够条件性敲除 GSK-3¿ 和 GSK-3¿ 的小鼠。
我们希望测试的具体假设是 GSK-3 失活会减少 β-淀粉样肽的产生
并预防 AD 病理的发生。这些小鼠以及源自这些小鼠的细胞将使我们能够
开始研究 GSK-3 活性如何影响 AD 发病机制的分子基础,
神经变性。
具体目标 1:定义每种 GSK-3 同工型对导致以下疾病发病机制的事件的贡献:
阿尔茨海默病。
具体目标 2:描述 GSK-3¿ 和 GSK-3¿ 对
β-淀粉样肽的生产。
具体目标 3:检查有条件删除 GSK-3¿ 和 GSK-3¿ 对发病机制的影响
阿尔茨海默病。
上述目标利用我们的新型 GSK-3 条件敲除小鼠,从而为我们提供了机会
在理解 GSK-3 亚型的分子机制方面取得重大进展
参与阿尔茨海默病。该申请提出了旨在更好地了解阿尔茨海默病如何发生的实验
发展。我们希望,这些知识的增加将导致能够开发出能够治疗的疗法。
减缓或预防与阿尔茨海默病相关的症状。
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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CHRISTOPHER J PHIEL其他文献
CHRISTOPHER J PHIEL的其他文献
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{{ truncateString('CHRISTOPHER J PHIEL', 18)}}的其他基金
The Regulation of mRNA Methylation by Glycogen Synthase Kinase-3
糖原合酶激酶3对mRNA甲基化的调控
- 批准号:
9813412 - 财政年份:2016
- 资助金额:
$ 0.61万 - 项目类别:
The Regulation of mRNA Methylation by Glycogen Synthase Kinase-3
糖原合酶激酶3对mRNA甲基化的调控
- 批准号:
9099331 - 财政年份:2016
- 资助金额:
$ 0.61万 - 项目类别:
Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
- 批准号:
8067895 - 财政年份:2008
- 资助金额:
$ 0.61万 - 项目类别:
Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
- 批准号:
7866484 - 财政年份:2008
- 资助金额:
$ 0.61万 - 项目类别:
Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
- 批准号:
8616432 - 财政年份:2008
- 资助金额:
$ 0.61万 - 项目类别:
Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
- 批准号:
7533794 - 财政年份:2008
- 资助金额:
$ 0.61万 - 项目类别:
Effects of Conditional GSK3 Knockout on the Pathogenesis of Alzheimers Disease
条件性 GSK3 敲除对阿尔茨海默病发病机制的影响
- 批准号:
7666814 - 财政年份:2008
- 资助金额:
$ 0.61万 - 项目类别:
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