Alzheimer's Disease and Impaired APP Proteolysis
阿尔茨海默病和 APP 蛋白水解受损
基本信息
- 批准号:7140287
- 负责人:
- 金额:$ 19.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-01 至 2007-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Familial Alzheimer's Disease (FAD) is a genetically heritable dominant disorder. Specific missense mutations that result in a single amino acid substitution in p-amyloid precursor protein (APR) have been linked with FAD. FAD mutations in APP cluster around two regions, the extracellular domain adjacent to the a- and (3-secretase sites, and within the intramembranous region adjacent to known y-secretase cleavage sites. The goal of this proposal is to study the effects of FAD mutations upon y-secretase mediated cleavage of APP in the brains of intact mice. The approach involves the development of a trarisgenic mouse model employing a y-secretase activity reporter system previously developed and validated in vitro. Using this screen in cell culture systems, we have demonstrated that FAD mutations result in a decrement in liberation of the APP carboxy-terminus resulting from APP cleavage. While this data is compelling, it remains to be tested whether decrements in y-secretase-mediated APP cleavage are a common effect of FAD mutations within intact brain. This project will test the hypothesis that FAD mutations decrease y-secretase- mediated proteolytic liberation of the carboxy-terminal fragment of APP from the membrane in brain under physiological conditions. The Specific Aims are: 1) Develop a transgenic reporter mouse model to assay y-secretase activity in vivo. Transgenic mouse lines will be developed expressing the APP-Ga!4VP16 activator under the control of the elongation factor 1 alpha (EF1a) promoter, and crossed with Gal4- luciferaseEGFP transgenic mice. Successful deployment of the genetic screening system, and the y-secretase dependency of the reporter output, will be validated by histological and reporter assay methods. 2) Compare y-secretase-mediated cleavage of wild-type and FAD mutant APP-Gal4VP16 using the transgenic reporter mouse model. FAD mutant APP-Gal4VP16 transgenic lines will be crossed with Gal4- luciferaseEGFP reporter mice, and comparative analysis of the reporter output of the wild-type and FAD mutants will be used to determine relative y-secretase activity in each set of transgenic: lines.
描述(申请人提供):家族性阿尔茨海默病(FAD)是一种遗传性显性疾病。导致β-淀粉样前体蛋白(APR)中单个氨基酸取代的特定错义突变与FAD有关。APP中的FAD突变聚集在两个区域周围,即邻近α-和β-分泌酶位点的细胞外结构域和邻近已知γ-分泌酶切割位点的膜内区域。本提案的目的是研究FAD突变对完整小鼠脑中γ-分泌酶介导的APP切割的影响。该方法涉及开发一个trapezogenic小鼠模型,采用以前开发和体外验证的γ-分泌酶活性报告系统。在细胞培养系统中使用该筛选,我们已经证明FAD突变导致APP羧基末端由APP切割产生的释放减少。虽然这一数据是令人信服的,它仍然有待测试是否在γ-分泌酶介导的APP裂解的递减是完整的大脑内的FAD突变的共同影响。本项目将测试以下假设:在生理条件下,FAD突变减少γ-分泌酶介导的APP羧基末端片段从脑中膜的蛋白水解释放。具体目的是:1)建立γ-分泌酶活性检测的转基因小鼠模型。将开发表达APP-Ga!4VP 16激活剂在延伸因子1 α(EF 1a)启动子的控制下,并与Gal 4-β-D-内切酶EGFP转基因小鼠杂交。将通过组织学和报告基因测定方法验证遗传筛选系统的成功部署以及报告基因输出的γ-分泌酶依赖性。2)使用转基因报告小鼠模型比较γ-分泌酶介导的野生型和FAD突变体APP-Gal 4VP 16的切割。将FAD突变体APP-Gal 4VP 16转基因系与Gal 4-β-分泌酶EGFP报道小鼠杂交,并将野生型和FAD突变体的报道输出的比较分析用于确定每组转基因系中的相对γ-分泌酶活性。
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 }}
Warren C LADIGES其他文献
Warren C LADIGES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('Warren C LADIGES', 18)}}的其他基金
Physical resilience is a predictor of healthy aging
身体弹性是健康衰老的预测指标
- 批准号:
10731992 - 财政年份:2017
- 资助金额:
$ 19.37万 - 项目类别:
Physical resilience is a predictor of healthy aging in mice
身体恢复能力是小鼠健康衰老的预测因素
- 批准号:
9418968 - 财政年份:2017
- 资助金额:
$ 19.37万 - 项目类别:
Physical resilience is a predictor of healthy aging in mice
身体恢复能力是小鼠健康衰老的预测因素
- 批准号:
10166752 - 财政年份:2017
- 资助金额:
$ 19.37万 - 项目类别:
Mitochondrial catalase as a treatment for metastatic breast cancer
线粒体过氧化氢酶治疗转移性乳腺癌
- 批准号:
7707170 - 财政年份:2009
- 资助金额:
$ 19.37万 - 项目类别:
相似国自然基金
新型F-18标记香豆素衍生物PET探针的研制及靶向Alzheimer's Disease 斑块显像研究
- 批准号:81000622
- 批准年份:2010
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
阿尔茨海默病(Alzheimer's disease,AD)动物模型构建的分子机理研究
- 批准号:31060293
- 批准年份:2010
- 资助金额:26.0 万元
- 项目类别:地区科学基金项目
跨膜转运蛋白21(TMP21)对引起阿尔茨海默病(Alzheimer'S Disease)的γ分泌酶的作用研究
- 批准号:30960334
- 批准年份:2009
- 资助金额:22.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Pathophysiological mechanisms of hypoperfusion in mouse models of Alzheimer?s disease and small vessel disease
阿尔茨海默病和小血管疾病小鼠模型低灌注的病理生理机制
- 批准号:
10657993 - 财政年份:2023
- 资助金额:
$ 19.37万 - 项目类别:
Social Connectedness and Communication in Parents with Huntington''s Disease and their Offspring: Associations with Psychological and Disease Progression
患有亨廷顿病的父母及其后代的社会联系和沟通:与心理和疾病进展的关联
- 批准号:
10381163 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease
更年期驱动的 DNA 损伤和表观遗传失调在阿尔茨海默病中的作用
- 批准号:
10531959 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
The Role of Menopause-Driven DNA Damage and Epigenetic Dysregulation in Alzheimer s Disease
更年期驱动的 DNA 损伤和表观遗传失调在阿尔茨海默病中的作用
- 批准号:
10700991 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
Interneurons as early drivers of Huntington´s disease progression
中间神经元是亨廷顿病进展的早期驱动因素
- 批准号:
10518582 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
Interneurons as Early Drivers of Huntington´s Disease Progression
中间神经元是亨廷顿病进展的早期驱动因素
- 批准号:
10672973 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
Social Connectedness and Communication in Parents with Huntington''s Disease and their Offspring: Associations with Psychological and Disease Progression
患有亨廷顿病的父母及其后代的社会联系和沟通:与心理和疾病进展的关联
- 批准号:
10585925 - 财政年份:2022
- 资助金额:
$ 19.37万 - 项目类别:
Oligodendrocyte heterogeneity in Alzheimer' s disease
阿尔茨海默病中的少突胶质细胞异质性
- 批准号:
10180000 - 财政年份:2021
- 资助金额:
$ 19.37万 - 项目类别:
Serum proteome analysis of Alzheimer´s disease in a population-based longitudinal cohort study - the AGES Reykjavik study
基于人群的纵向队列研究中阿尔茨海默病的血清蛋白质组分析 - AGES 雷克雅未克研究
- 批准号:
10049426 - 财政年份:2021
- 资助金额:
$ 19.37万 - 项目类别:
Repurposing drugs for Alzheimer´s disease using a reverse translational approach
使用逆翻译方法重新利用治疗阿尔茨海默病的药物
- 批准号:
10295809 - 财政年份:2021
- 资助金额:
$ 19.37万 - 项目类别:














{{item.name}}会员




