microRNA (miRNA) signaling in Alzheimer's disease(AD)

阿尔茨海默病 (AD) 中的 microRNA (miRNA) 信号传导

基本信息

  • 批准号:
    9916675
  • 负责人:
  • 金额:
    $ 36.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-01 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

microRNA (miRNA) signaling in Alzheimer's disease (AD) Through extensive miRNA- and DNA-based expression array-, LED-Northern-, ELISA, Western-, immunological and bioinformatics-based analysis we have discovered a highly interactive network of NF-kB sensitive, up-regulated pro-inflammatory microRNAs (miRNAs) and their down-regulated messenger RNA (mRNA) targets and the proteins these mRNAs encode in sporadic Alzheimer's disease (AD) brain. The up-regulation of these pathogenic miRNAs and their down-regulated mRNA targets has been further analyzed in stressed human brain cells in primary culture and in 5xFAD amyloid over-expressing transgenic mouse lines. Through miRNA and mRNA abundance analysis, miRNA-mRNA complementarity mapping, association energy (EA) indexing, ELISA and Western analysis we can explain much of the observed neuropathology characteristic of the AD process by analyzing significant disruptions in selective miRNA-mRNA signaling. Our hypothesis is that there exists a small family of at least 6 critical pro-inflammatory miRNAs in AD brains responsible for targeting and down-regulating a group of pathogenic messenger RNA (mRNA) targets responsible for amyloidogenesis, tau pathology and neuroinflammation with accompanying deficits in synaptogenesis, innate- immunity, phagocytosis and a progressive impairment in Aβ42 peptide clearance. This renewal of our previous 5 year NIA R01 will investigate the integrated actions of this group of 6 pro-inflammatory, pathogenic miRNAs up-regulated in sporadic AD brain, in stressed human brain cells in primary culture in the brains of 5xFAD mice. The 6 up-regulated pro- inflammatory microRNAs to be studied in detail are miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. Stressors will be those encountered as are found in aging AD brain – these include reactive oxygen species (ROS), the pro-inflammatory cytokines IL-1β and TNFα and Aβ42 peptides. Specific Aim 1 will analyze the contribution of these factors in moderate-to- advanced sporadic AD and Down's syndrome (DS) brain; Specific Aim 2 will analyze the contribution of these factors in stressed human brain cells, i.e. in neuronal-glial primary cell co- cultures; Specific Aim 3 will analyze the contribution of these factors in 5xFAD amyloid over- expressing transgenic mouse lines. We will specifically accentuate the study of the most up- regulated miRNAs: miRNA-7, miRNA-9, miRNA 34a and miRNA-146a and their targeted disruption of UBE2A (ubiquitin conjugase protein) and TREM2 (triggering receptor expressed in microglial cells) signaling in AD brain, and in in vitro and in vivo AD models. We will also analyze the applicability of selective NF-kB inhibitors and anti-miRNA (AM) strategies in restoring homeostasis in this system. Our long term goal is the therapeutic manipulation of these miRNA-regulated epigenetic pathways to provide an efficacious treatment for the clinical management of AD at an early stage.
阿尔茨海默病(AD)中的microRNA(miRNA)信号传导 通过广泛的基于miRNA和DNA的表达阵列、LED Northern、ELISA, 基于Western,免疫学和生物信息学的分析,我们发现了一个高度 NF-κ B敏感性、上调的促炎microRNAs(miRNAs)的相互作用网络 以及它们下调的信使RNA(mRNA)靶点和这些mRNA的蛋白质 散发性阿尔茨海默病(AD)大脑中的编码。这些致病基因的上调 miRNAs及其下调的mRNA靶点在应激的人类中得到了进一步的分析。 原代培养物中的脑细胞和5xFAD淀粉样蛋白过表达转基因小鼠系中的脑细胞。 通过miRNA和mRNA丰度分析,miRNA-mRNA互补作图, 结合能量(EA)指数,ELISA和Western分析,我们可以解释大部分的 观察AD过程的神经病理学特征,通过分析 选择性miRNA-mRNA信号传导。我们的假设是存在一个至少6人的小家庭, AD大脑中负责靶向和下调 一组负责淀粉样蛋白生成的致病信使RNA(mRNA)靶标,tau 病理学和神经炎症伴随突触发生缺陷,先天性, 免疫、吞噬作用和Aβ42肽清除的进行性损害。 我们之前的5年NIA R 01的更新将调查此 一组6种促炎性、致病性miRNA在散发性AD脑中上调,在应激性AD脑中上调, 在5xFAD小鼠脑中的原代培养物中的人脑细胞。6个上调的亲- 待详细研究的炎性微RNA是miRNA-7、miRNA-9、miRNA-34 a、miRNA-125 b, miRNA-146 a和miRNA-155。压力源将是那些在老化的AD大脑中发现的压力源 - 这些包括活性氧(ROS)、促炎细胞因子IL-1β和TNFα 和Aβ42肽。具体目标1将分析这些因素在中度至中度 晚期散发性AD和唐氏综合征(DS)大脑;具体目标2将分析 这些因子在应激人脑细胞中的作用,即在神经元-神经胶质原代细胞中的作用, 具体目标3将分析这些因素在5xFAD淀粉样蛋白中的作用, 表达转基因小鼠品系。我们将特别强调对最高层的研究- 调节的miRNA:miRNA-7、miRNA-9、miRNA 34 a和miRNA-146 a及其靶向的 UBE 2A(泛素缀合酶蛋白)和TREM 2(在细胞中表达的触发受体)的破坏 在AD脑中以及在体外和体内AD模型中的微胶质细胞)信号传导。我们还将 分析选择性NF-κ B抑制剂和抗miRNA(AM)策略在 恢复这个系统的平衡我们的长期目标是治疗操纵 这些miRNA调节的表观遗传途径为临床提供了有效的治疗。 在早期阶段管理AD。

项目成果

期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer's Disease.
  • DOI:
    10.1007/s12035-018-1040-x
  • 发表时间:
    2019-01
  • 期刊:
  • 影响因子:
    5.1
  • 作者:
    Jęśko H;Wencel PL;Lukiw WJ;Strosznajder RP
  • 通讯作者:
    Strosznajder RP
Inhibition of Poly(ADP-ribose) Polymerase-1 Enhances Gene Expression of Selected Sirtuins and APP Cleaving Enzymes in Amyloid Beta Cytotoxicity.
  • DOI:
    10.1007/s12035-017-0646-8
  • 发表时间:
    2018-06
  • 期刊:
  • 影响因子:
    5.1
  • 作者:
    Wencel PL;Lukiw WJ;Strosznajder JB;Strosznajder RP
  • 通讯作者:
    Strosznajder RP
Biomarkers for Alzheimer's Disease (AD) and the Application of Precision Medicine.
  • DOI:
    10.3390/jpm10030138
  • 发表时间:
    2020-09-21
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Lukiw WJ;Vergallo A;Lista S;Hampel H;Zhao Y
  • 通讯作者:
    Zhao Y
Differential expression of miRNA-146a-regulated inflammatory genes in human primary neural, astroglial and microglial cells.
  • DOI:
    10.1016/j.neulet.2011.05.044
  • 发表时间:
    2011-07-20
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Li YY;Cui JG;Dua P;Pogue AI;Bhattacharjee S;Lukiw WJ
  • 通讯作者:
    Lukiw WJ
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Nicolas G. Bazan其他文献

Localization of lipocalin-type prostaglandin D synthase (beta-trace) in iris, ciliary body, and eye fluids.
脂质运载蛋白型前列腺素 D 合酶(β-痕量)在虹膜、睫状体和眼液中的定位。
  • DOI:
  • 发表时间:
    1998
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    D. Gerashchenko;C. T. Beuckmann;V. Marcheselli;William C. Gordon;Y. Kanaoka;Naomi Egucbi;Y. Urade;O. Hayaishi;Nicolas G. Bazan
  • 通讯作者:
    Nicolas G. Bazan
Diffusion of intracerebrally injected [1-14C]arachidonic acid and [2-3H]Glycerol in the mouse brain
  • DOI:
    10.1007/bf00965088
  • 发表时间:
    1982-12-01
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Maria F. Pediconi;Elena B. Rodriguez de Turco;Nicolas G. Bazan
  • 通讯作者:
    Nicolas G. Bazan
The Optimization of a Natural Language Processing Approach for the Automatic Detection of Alzheimer’s Disease Using GPT Embeddings
使用 GPT 嵌入优化自动检测阿尔茨海默病的自然语言处理方法
  • DOI:
    10.3390/brainsci14030211
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Benjamin S. Runde;Ajit Alapati;Nicolas G. Bazan
  • 通讯作者:
    Nicolas G. Bazan
Composition and metabolism of phospholipids during earyly stages of vertebrate embryonic development.
脊椎动物胚胎发育早期阶段磷脂的组成和代谢。
  • DOI:
    10.1007/978-1-4684-3276-3_23
  • 发表时间:
    1977
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. M. P. D. D’Angelo;I. C. B. D. Romanelli;Telma S. Alonso;Nicolas G. Bazan
  • 通讯作者:
    Nicolas G. Bazan
Regulation of arachidonic acid metabolism in the perinatal brain during development and under ischemic stress.
发育期间和缺血应激下围产期大脑花生四烯酸代谢的调节。

Nicolas G. Bazan的其他文献

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{{ truncateString('Nicolas G. Bazan', 18)}}的其他基金

Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
  • 批准号:
    10395594
  • 财政年份:
    2019
  • 资助金额:
    $ 36.5万
  • 项目类别:
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
  • 批准号:
    10221785
  • 财政年份:
    2019
  • 资助金额:
    $ 36.5万
  • 项目类别:
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
  • 批准号:
    10606600
  • 财政年份:
    2019
  • 资助金额:
    $ 36.5万
  • 项目类别:
Docosanoids modulate homeostasis and cell survival after ischemic stroke
二十二烷酸调节缺血性中风后的体内平衡和细胞存活
  • 批准号:
    9815688
  • 财政年份:
    2019
  • 资助金额:
    $ 36.5万
  • 项目类别:
Novel combinatory therapy for experimental ischemic stroke
实验性缺血性中风的新型组合疗法
  • 批准号:
    10330435
  • 财政年份:
    2018
  • 资助金额:
    $ 36.5万
  • 项目类别:
Novel combinatory therapy for experimental ischemic stroke
实验性缺血性中风的新型组合疗法
  • 批准号:
    10093153
  • 财政年份:
    2018
  • 资助金额:
    $ 36.5万
  • 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
  • 批准号:
    9068162
  • 财政年份:
    2012
  • 资助金额:
    $ 36.5万
  • 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
  • 批准号:
    8853292
  • 财政年份:
    2012
  • 资助金额:
    $ 36.5万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8479230
  • 财政年份:
    2012
  • 资助金额:
    $ 36.5万
  • 项目类别:
Mentoring Neuroscience in Louisiana: A Biomedical Program to Enhance Neuroscience
路易斯安那州的神经科学指导:增强神经科学的生物医学计划
  • 批准号:
    8536885
  • 财政年份:
    2012
  • 资助金额:
    $ 36.5万
  • 项目类别:

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