APP GENE PROMOTER IN ALZHEIMER'S DISEASE

阿尔茨海默病中的 APP 基因启动子

基本信息

项目摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) Misregulation of transcription of theB-amyloid precursor protein (APP) gene is implicated in the Pathogenesis of Alzheimer's disease (AD). Several early studies indicated that the APP gene expression might be increased in AD brains. That increases in the APP expression can lead to AD is strongly suggested by its high incidence in Down's syndrome patients with three copies of the gene. AD is a complex disorder with potentially multiple triggers. It is quite possible that disturbance in the transcriptional regulation of APP affects a subset of AD patients. Alternatively, failure to observe consistently a detectable increase in APP mRNA in post-mortem brains may be due to a transient over expression of APP, which may lead to nucleation of amyloid plaques. Our hypothesis is that the APP regulatory pathways play a critical role in AD pathogenesis. Our long-term goal is to study the transcriptional control of the APP gene. We have recently cloned and characterized a 7.9 kb APP promoter region. Here we will examine the role of the upstream regulatory elements (URE) on APP promoter activity and in late-onset AD. This proposal is based on our novel finding that a -75 to +104 bp region regulates APP promoter activity in a cell-type specific manner. The specific aims are: 1) To determine the coredomain of APP promoter that is essential for its activity and indelibility. Certain upstream regulatory regions that confer basic promoter activity in neurons and astrocytes may respond to activation by growth factors and cytokines, which are produced by activated macrophages during the inflammatory response in AD. Functional characterization of the regulatory regions will be done by a serial deletion strategy and DNA transfection in cell lines and primary cultures. 2) To identify whether URE interacts with a cell type specific nuclear protein. We will study how the specific upstream region interacts with a cell type-specific factor in neurons and astrocytes and how this interaction will be affected in the presence of cytokines and growth factors. 3) To determine the role of URE in the developmental and disease state. Differential effects of the promoter region in cell types might suggest a role for URE during development and differentiation. We plan to examine the levels of URE-binding factor in developmental rat brains, normal and AD brains. 4) To determine the genetic variability of the regulatory region in AD. The genetic variability of the regulatory region may be important for late-onset AD sporadic subjects. We propose to screen genomic DNA for 'promoter elements' and to compare the 'promoter binding factors' in control and AD subjects. 5) To manipulate promoter activity in cell culture. We plan to modify the specific regulatory effect of the APP promoter by in vivo competition experiment and using the antisense oligodeoxynucleotide strategy. Finally, we will correlate promoter studies with levels of APP and AB in control and AD subjects. Understanding the complex interplay between the promoter domains and the transcription factors may suggest novel methods for therapeutic intervention.
描述:(逐字摘自申请者的摘要)管理不当 β-淀粉样前体蛋白(APP)基因的转录参与了 阿尔茨海默病(AD)的发病机制。早期的几项研究表明 阿尔茨海默病患者脑内APP基因表达可能增加。这增加了 APP表达可导致AD强烈提示其在 唐氏综合症患者携带三个拷贝的基因。广告是一种复杂的东西 可能有多个诱因的疾病。很有可能 APP转录调控障碍影响AD的一个子集 病人。或者,未能持续观察到可检测到的增长 死后脑内APP mRNA的表达可能是由于一过性过表达 APP,可能导致淀粉样斑块的核化。我们的假设是 APP调控通路在AD发病机制中起着关键作用。我们的 长期目标是研究APP基因的转录控制。我们有 最近克隆并鉴定了一个7.9kb的APP启动子区域。在这里,我们将 考察上游调控元件(URE)对APP启动子的作用 活动性和晚发性AD。这项建议是基于我们的新发现 A-75~+104碱基区调控特定细胞类型APP启动子活性 举止。具体目的是:1)确定APP启动子的核心结构域 这对于它的活力和不可磨灭是必不可少的。某些上游 在神经元中赋予基本启动子活性的调节区 星形胶质细胞可能对生长因子和细胞因子的激活做出反应,这两种因子是 在AD的炎症反应过程中由激活的巨噬细胞产生。 监管区域的功能特征将通过一系列 缺失策略和DNA在细胞系和原代培养中的导入。2) 以确定URE是否与一种细胞类型的特定核蛋白相互作用。我们 将研究特定的上游区域如何与特定类型的细胞相互作用 神经元和星形胶质细胞中的因子以及这种相互作用将如何在 细胞因子和生长因子的存在。3)确定城市资源中心的角色 处于发育和疾病状态。启动子的差异化效应 细胞类型中的区域可能表明URE在发育和 差异化。我们计划检查尿素结合因子的水平在 发育期大鼠脑、正常脑和AD脑。4)确定基因 AD中调控区域的可变性。人类基因组的遗传变异性 调节区可能对迟发性AD散发性受试者很重要。我们 建议筛选基因组DNA中的“启动子元件”,并比较 对照组和AD受试者中的“启动子结合因子”。5)操纵 细胞培养中的启动子活性。我们计划修改具体的监管规定 APP启动子在体内竞争实验中的作用 反义寡核苷酸策略。最后,我们将关联启动子 对照组和AD患者APP和AB水平的研究。了解 启动子结构域与转录因子之间的复杂相互作用 可能会为治疗干预提供新的方法。

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(3)

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 }}

DEBOMOY K LAHIRI其他文献

DEBOMOY K LAHIRI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('DEBOMOY K LAHIRI', 18)}}的其他基金

Alzheimer's disease-linked microRNA Exploration of UTR Polymorphisms (AdmiRE-UP)
阿尔茨海默病相关 microRNA UTR 多态性探索 (AdMRE-UP)
  • 批准号:
    10391153
  • 财政年份:
    2022
  • 资助金额:
    $ 29万
  • 项目类别:
Brain protein alteration by vascular overexpressed miRNA (BravomiR)
血管过度表达 miRNA (BravomiR) 改变脑蛋白
  • 批准号:
    10392051
  • 财政年份:
    2022
  • 资助金额:
    $ 29万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10666628
  • 财政年份:
    2021
  • 资助金额:
    $ 29万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10264437
  • 财政年份:
    2021
  • 资助金额:
    $ 29万
  • 项目类别:
Role of microRNA in regulating Fe, Amyloid, and Tau (FeAT) in Alzheimer's disease
microRNA 在阿尔茨海默病中调节 Fe、淀粉样蛋白和 Tau (FeAT) 的作用
  • 批准号:
    10460800
  • 财政年份:
    2021
  • 资助金额:
    $ 29万
  • 项目类别:
Research Education Component
研究教育部分
  • 批准号:
    10475196
  • 财政年份:
    2021
  • 资助金额:
    $ 29万
  • 项目类别:
Testing a Novel Approach to Solve the On-target, Off-site Effects of Alzheimer's Drugs
测试一种解决阿尔茨海默病药物的在靶、异位效应的新方法
  • 批准号:
    9456159
  • 财政年份:
    2019
  • 资助金额:
    $ 29万
  • 项目类别:
Administrative Supplement: Neurobiological role of MicroRNA in Alzheimer's
行政补充:MicroRNA 在阿尔茨海默病中的神经生物学作用
  • 批准号:
    9321507
  • 财政年份:
    2015
  • 资助金额:
    $ 29万
  • 项目类别:
Neurobiological Role of MicroRNA in Alzheimer's
MicroRNA 在阿尔茨海默病中的神经生物学作用
  • 批准号:
    9134034
  • 财政年份:
    2015
  • 资助金额:
    $ 29万
  • 项目类别:
Neurobiological Role of MicroRNA in Alzheimer's
MicroRNA 在阿尔茨海默病中的神经生物学作用
  • 批准号:
    10901008
  • 财政年份:
    2015
  • 资助金额:
    $ 29万
  • 项目类别:

相似海外基金

Solid State NMR Studies of Amyloid Proteins
淀粉样蛋白的固态核磁共振研究
  • 批准号:
    10446323
  • 财政年份:
    2017
  • 资助金额:
    $ 29万
  • 项目类别:
Solid State NMR Studies of Amyloid Proteins
淀粉样蛋白的固态核磁共振研究
  • 批准号:
    10687158
  • 财政年份:
    2017
  • 资助金额:
    $ 29万
  • 项目类别:
Solid State NMR Studies of Amyloid Proteins
淀粉样蛋白的固态核磁共振研究
  • 批准号:
    9366854
  • 财政年份:
    2017
  • 资助金额:
    $ 29万
  • 项目类别:
Development of aggregation inhibition strategy for pathogenic amyloid proteins
致病性淀粉样蛋白聚集抑制策略的开发
  • 批准号:
    16H06216
  • 财政年份:
    2016
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Young Scientists (A)
Elucidation of the mechanisms on aggregation and toxicity of plant amyloid proteins which are toxic in the presence of metals
阐明在金属存在下有毒的植物淀粉样蛋白的聚集和毒性机制
  • 批准号:
    23380192
  • 财政年份:
    2011
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Demonstration of the abnormal conformational transition of amyloid proteins and it's application as an early diagnostic tool
淀粉样蛋白异常构象转变的演示及其作为早期诊断工具的应用
  • 批准号:
    21200072
  • 财政年份:
    2009
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
Metabolism of amyloid proteins and methods for detecting amyloid proteins
淀粉样蛋白的代谢和检测淀粉样蛋白的方法
  • 批准号:
    21790541
  • 财政年份:
    2009
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Development of aggregation disrupters for amyloid proteins
淀粉样蛋白聚集破坏剂的开发
  • 批准号:
    17310132
  • 财政年份:
    2005
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Inhibition of axonal transport of hippocampal neurons by amyloid proteins: relation to Alzheimer's disease
淀粉样蛋白抑制海马神经元轴突运输:与阿尔茨海默病的关系
  • 批准号:
    11670638
  • 财政年份:
    1999
  • 资助金额:
    $ 29万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
RAB GTPASES AND TRAFFICKING OF BETA AMYLOID PROTEINS
RAB GTP 酶和 β 淀粉样蛋白的贩运
  • 批准号:
    6149928
  • 财政年份:
    1998
  • 资助金额:
    $ 29万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了