Regulation of Presenilin Genes
早老素基因的调控
基本信息
- 批准号:6909933
- 负责人:
- 金额:$ 29.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-01 至 2009-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The objective of this project is to test the hypothesis that deregulation of genes for presenilins (PSs) and PS- interacting proteins contributes to Alzheimer's disease (AD) pathology. Missense-mutations in two homologous presenilin genes, PS1 and PS2, are the major cause of familial early onset Alzheimer's disease (AD). The role of these genes in the most common, the late-onsetAD, remains to be elucidated. PSs are involved in the proteolytic cleavage of several proteins, eg., amyloid precursor protein (APP), that is thought to be critical factor in molecular cascade mechanisms leading to AD. AD-associated mutations enhance this cleavage, while the abolishment of PS1 and PS2 activity inhibits the endoproteolysis of APP substrate. It is conceivable, then, that alteration of expression of PSs modulate AD pathology. Our preliminary data suggest hypoxia is an important factor in regulation of genes for PSs and PS- interacting proteins. The data strongly suggest that PS2 is highly inducible by hypoxia/hyperoxia conditions and that alteration of regulatory DNA elements (IRF2/CREBB) in PS2 increases the susceptibility of the promoter region to stress-regulated factors associated with AD. We also identified a novel family of presenilin-homologous proteins and highly regulated presenilin isoforms lacking functional domains. We hypothesize that activity of PSs is modulated by 1) transcriptional factors, including naturally-occurring DNA variations and stress-regulated DNA elements; and 2) post-transcriptional factors, including PS-like protein isoforms with putative dominant negative effects. The goal of this proposal is to elucidate molecular factors that regulate presenilins on transcriptional and posttranslational levels. We will 1) identify novel-molecular-genetic factors (gene haplotypes) contributing to AD; 2) isolate novel transcription and splicing enhancer/repressor elements that dynamically regulate PSs; 3) elucidate the role of newly identified PS-homologous proteins in modulation of processing or expression of PS proteins. We present a convergent approach with which the genetic analysis of AD patients will be accompanied by phylogenic and functional analysis of the gene variations in vitro. To achieve these goals, methods of genetic association analysis, molecular assays for quantitative evaluation of promoter activities, and protein processing in mammalian cells, cellular assays for exon trapping and PS-mediated proteolysis will be undertaken. The accomplishment of these goals will clarify molecular-genetic and epigenetic mechanisms of AD. These studies will contribute to identification of molecular factors regulating the primary causes of AD, and ultimately, to the development of new strategies for prevention and rational therapy of Alzheimer's disease.
描述(由申请人提供):本项目的目的是检验早老素(PS)和PS相互作用蛋白基因的失调有助于阿尔茨海默病(AD)病理学的假设。早老素基因PS1和PS2的错义突变是家族性早发性阿尔茨海默病(AD)的主要病因。这些基因在最常见的迟发性AD中的作用仍有待阐明。PS参与几种蛋白质的蛋白水解切割,例如,淀粉样前体蛋白(APP),其被认为是导致AD的分子级联机制中的关键因子。AD相关突变增强了这种切割,而PS1和PS2活性的废除抑制APP底物的内蛋白水解。因此,可以想象,PS表达的改变调节AD病理。我们的初步数据表明,缺氧是一个重要的因素,在调节基因的PS和PS相互作用蛋白。这些数据有力地表明,PS2是高度诱导的缺氧/高氧条件下,在PS2的调节DNA元件(IRF 2/CREBB)的改变增加了易感性的启动子区域与AD相关的应力调节因子。我们还确定了一个新的早老素同源蛋白家族和高度调控的早老素亚型缺乏功能结构域。我们假设PS的活性受1)转录因子,包括天然存在的DNA变异和应激调控的DNA元件;和2)转录后因子,包括具有推定显性负效应的PS样蛋白异构体。本研究的目的是阐明在转录和翻译后水平调控早老素的分子因子。我们将1)确定新的分子遗传因子(基因单倍型)有助于AD; 2)分离新的转录和剪接增强子/阻遏子元件,动态调节PS; 3)阐明新鉴定的PS同源蛋白在调节PS蛋白的加工或表达中的作用。我们提出了一个收敛的方法,AD患者的遗传分析将伴随着体外基因变异的遗传和功能分析。为了实现这些目标,将进行遗传关联分析、用于定量评价启动子活性的分子测定和哺乳动物细胞中的蛋白质加工、用于外显子捕获和PS介导的蛋白质水解的细胞测定的方法。这些目标的实现将有助于阐明AD的分子遗传学和表观遗传学机制。这些研究将有助于确定调节AD主要病因的分子因素,并最终为预防和合理治疗阿尔茨海默病制定新的策略。
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 }}
EVGENY I ROGAEV其他文献
EVGENY I ROGAEV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('EVGENY I ROGAEV', 18)}}的其他基金
Epigenetic-Genetic Modulations in Aging and Alzheimer's Disease Neurons
衰老和阿尔茨海默病神经元的表观遗传-遗传调节
- 批准号:
9910352 - 财政年份:2017
- 资助金额:
$ 29.97万 - 项目类别:
Molecular-Genetic Mechanisms for Early-Onset Obesity
早发性肥胖的分子遗传学机制
- 批准号:
7091344 - 财政年份:2004
- 资助金额:
$ 29.97万 - 项目类别:
Molecular-Genetic Mechanisms for Early-Onset Obesity
早发性肥胖的分子遗传学机制
- 批准号:
6951476 - 财政年份:2004
- 资助金额:
$ 29.97万 - 项目类别:
Molecular-Genetic Mechanisms for Early-Onset Obesity
早发性肥胖的分子遗传学机制
- 批准号:
6820274 - 财政年份:2004
- 资助金额:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 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:
$ 29.97万 - 项目类别: