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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：
CHRISTOPHER J PHIEL
金额：
$ 0.61万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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：
https://reporter.nih.gov/project-details/8286953
关键词：
Address Affect Affinity Chromatography Alzheimer disease prevention Alzheimer&apos s Disease Amyloid beta-Protein Precursor Binding Brain Cells Cognitive Dementia Deposition Deterioration Development Diagnosis Disease Event Generations Genetic Recombination Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Grant Health Intervention Investigation KRP protein Knock-out Knockout Mice Knowledge Laboratory Study Lead Link Mediating Mediator of activation protein Medical Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathogenesis Pathology Phosphotransferases Physiological Play Prevention Process Production Protein Isoforms Proteins Regulation Role Senile Plaques Series Structure Symptoms Testing Transgenic Mice United States amyloid peptide base defined contribution design hyperphosphorylated tau in vivo inhibitor/antagonist mouse model neurofibrillary tangle formation new therapeutic target novel overexpression prevent protein aggregate protein transport research study skills tau Proteins tau phosphorylation therapeutic 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。