Notch Functions in the Adult Nervous System

成人神经系统中的Notch功能

基本信息

  • 批准号:
    8010052
  • 负责人:
  • 金额:
    $ 29.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-15 至 2014-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Notch signaling plays well described roles in developmental cell fate decisions, in the regulation of stem cell proliferation and in numerous diseases. However, Notch signaling is also critical for the function of adult neurons. Notch plays a role in memory retention in mice and Drosophila, yet the targets of Notch signaling in neurons are unclear. We have demonstrated that the C. elegans lin-12 Notch receptor acts in adult animals to modulate behavior. In the studies proposed here, we will identify the molecular pathways by which Notch signaling alters neuronal function and behavior using the powerful genetic techniques available in C. elegans. In a pilot screen, we identified five genes expressed in the nervous system that are likely direct targets of Notch. All five genes encode proteins that are likely critical for Notch signaling in vertebrate neurons as well. In this proposal, we address the mechanisms and pathways by which these Notch target genes act in the adult nervous system to regulate neuronal activity and behavior. PUBLIC HEALTH RELEVANCE: Notch signaling is critical for normal function of the human nervous system. Mutations in Notch3 and Jagged1 cause CADASIL and Alagille syndromes, respectively. These are dominantly inherited disorders associated with stroke and dementia. Combined, their incidence is at least 1 in 50,000, although CADASIL is likely under-diagnosed. Recent evidence also suggests that Notch signaling is up-regulated in Down's syndrome patients. Interestingly, Notch and amyloid precursor proteins directly interact suggesting that Notch signaling may be important in the memory defects associated with Alzheimer's disease. There is no effective treatment for these disorders. Given the conservation across species of Notch regulatory mechanisms and targets, we anticipate that identifying the targets of Notch signaling in C. elegans will reveal critical targets of Notch modulation in humans that are relevant in both normal and pathological conditions.
描述(由申请人提供):Notch信号在决定发育细胞命运、调节干细胞增殖和许多疾病中发挥着重要作用。然而,Notch信号对成年神经元的功能也是至关重要的。Notch在小鼠和果蝇的记忆保持中发挥了作用,但神经元中Notch信号的靶点尚不清楚。我们已经证明线虫LIN-12 Notch受体在成年动物中起调节行为的作用。在本文提出的研究中,我们将利用线虫强大的基因技术,确定Notch信号改变神经元功能和行为的分子途径。在试验性筛选中,我们确定了五个在神经系统中表达的基因,它们可能是Notch的直接靶标。所有五个基因都编码蛋白质,这些蛋白质可能对脊椎动物神经元中的Notch信号也至关重要。在这个提案中,我们讨论了这些Notch靶基因在成人神经系统中作用的机制和途径,以调节神经元的活动和行为。 公共卫生相关性:Notch信号对人类神经系统的正常功能至关重要。Notch3和Jagged1的突变分别导致CADASIL和Alagille综合征。这些主要是与中风和痴呆症相关的遗传性疾病。加在一起,他们的发病率至少为50000人中有1人,尽管CADASIL可能被低估了。最近的证据也表明,在唐氏综合症患者中,Notch信号上调。有趣的是,Notch和淀粉样前体蛋白直接相互作用,这表明Notch信号可能在与阿尔茨海默病相关的记忆缺陷中发挥重要作用。这些疾病没有有效的治疗方法。鉴于Notch调节机制和靶点在不同物种之间的保守性,我们预计识别线虫Notch信号的靶点将揭示人类Notch调节的关键靶点,这些靶点在正常和病理条件下都是相关的。

项目成果

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Anne Church Hart其他文献

Anne Church Hart的其他文献

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{{ truncateString('Anne Church Hart', 18)}}的其他基金

Examining cross-species suppression of neurodegeneration by loss of a conserved RNA binding protein in models of ALS and FTD
检查 ALS 和 FTD 模型中保守 RNA 结合蛋白缺失对神经退行性疾病的跨物种抑制
  • 批准号:
    10195707
  • 财政年份:
    2021
  • 资助金额:
    $ 29.19万
  • 项目类别:
Notch Functions in the Adult Nervous System
成人神经系统中的Notch功能
  • 批准号:
    8078195
  • 财政年份:
    2009
  • 资助金额:
    $ 29.19万
  • 项目类别:
Notch Functions in the Adult Nervous System
成人神经系统中的Notch功能
  • 批准号:
    7654805
  • 财政年份:
    2009
  • 资助金额:
    $ 29.19万
  • 项目类别:
Notch Functions in the Adult Nervous System
成人神经系统中的Notch功能
  • 批准号:
    8277201
  • 财政年份:
    2009
  • 资助金额:
    $ 29.19万
  • 项目类别:
Notch Functions in the Adult Nervous System
成人神经系统中的Notch功能
  • 批准号:
    8470720
  • 财政年份:
    2009
  • 资助金额:
    $ 29.19万
  • 项目类别:
Notch Functions in the Adult Nervous System
成人神经系统中的Notch功能
  • 批准号:
    7860665
  • 财政年份:
    2009
  • 资助金额:
    $ 29.19万
  • 项目类别:
Developmental analysis of SELCT proteins
SELCT蛋白的发育分析
  • 批准号:
    7426850
  • 财政年份:
    2007
  • 资助金额:
    $ 29.19万
  • 项目类别:
Developmental analysis of SELCT proteins
SELCT蛋白的发育分析
  • 批准号:
    8011484
  • 财政年份:
    2007
  • 资助金额:
    $ 29.19万
  • 项目类别:
Developmental analysis of SELCT proteins
SELCT蛋白的发育分析
  • 批准号:
    7849468
  • 财政年份:
    2007
  • 资助金额:
    $ 29.19万
  • 项目类别:
Developmental analysis of SELCT proteins
SELCT蛋白的发育分析
  • 批准号:
    7259972
  • 财政年份:
    2007
  • 资助金额:
    $ 29.19万
  • 项目类别:

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  • 批准号:
    19591584
  • 财政年份:
    2007
  • 资助金额:
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  • 项目类别:
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