Mechanism and therapy of AB-42-specific gamma-secretase

AB-42特异性γ-分泌酶的机制和治疗

基本信息

  • 批准号:
    8202120
  • 负责人:
  • 金额:
    $ 57.46万
  • 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:
    2011-06-01 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Due to the critical role of gamma-secretase in the generation of A? peptides, which are believed to be essential in Alzheimer's disease (AD) pathogenesis, gamma-secretase inhibitors have emerged as potential drug targets for AD. However, the wide spectrum of gamma-secretase substrates and the differential activities of the two major A? species, A?40 and A?42, in amyloid pathology have made gamma-secretase based therapy a formidable challenge. The combination of current understanding of the gamma-secretase biology with the recently failed clinical trial calls for the need to develop gamma-secretase inhibitors that specifically block A?42 production while leaving A?40 and other substrates intact. We have identified a series of compounds that exhibit these characteristics and they act through a distinct mechanism from that of A?42 gamma-secretase modulators. The overarching goal of this application is to elucidate the mechanism of action and therapeutic efficacy of A?42-specific gamma-secretase inhibition using an integrated approach of chemical biology, cell biology and animal models. We will develop a series of photoactivatable analogs to probe the molecular mechanisms of different mode of A?42 inhibition. We will determine their specificity and compare these with other classes of gamma-secretase inhibitors using novel cellular assays and in mice. Lastly, we will test the efficacy of A?42 specific inhibition on synaptic function and cognition in an AD knock-in mouse model. Overall, this proposal uses innovative approaches and model systems to address a topic highly significant in AD pathogenesis and therapeutic development. PUBLIC HEALTH RELEVANCE: Overwhelming evidence support a critical role of A?42 in AD pathogenesis. Accordingly, inhibition of gamma-secretase for A?42 production has emerged as an appealing therapeutic strategy for AD. This proposal directly addresses the mechanisms and functional role of A?42-specific inhibition in synaptic plasticity and learning and memory. It will greatly facilitate the understanding and development of ?-secretase-based AD therapy.
描述(申请人提供):由于伽马分泌酶在A的产生中的关键作用?多肽被认为在阿尔茨海默病(AD)的发病机制中是必不可少的,伽马分泌酶抑制剂已成为治疗AD的潜在药物靶点。然而,伽玛分泌酶底物的广谱和两种主要的A?淀粉样变病理中的A?40和A?42两个物种使基于伽马分泌酶的治疗成为一个艰巨的挑战。目前对伽玛分泌酶生物学的了解与最近失败的临床试验相结合,要求开发伽玛分泌酶抑制剂,这种抑制剂可以特异性地阻断A?42的产生,同时保持A?40和其他底物的完整性。我们已经鉴定了一系列表现出这些特征的化合物,它们通过与A?42伽马分泌酶调节剂不同的机制发挥作用。本研究的主要目的是利用化学生物学、细胞生物学和动物模型的综合方法来阐明A?42特异性的伽玛分泌酶抑制的作用机制和治疗效果。我们将开发一系列可光激活的类似物来探索不同模式的A42抑制的分子机制。我们将确定它们的特异性,并将它们与其他类别的伽马分泌酶抑制剂进行比较,使用新的细胞分析方法和在小鼠中进行比较。最后,我们将在AD敲入小鼠模型上测试A?42特异性抑制对突触功能和认知的影响。总体而言,该提案使用创新的方法和模型系统来解决AD发病机制和治疗开发中的一个非常重要的主题。 公共卫生相关性:压倒性证据支持A?42在AD发病机制中的关键作用。因此,抑制γ-分泌酶对A?42的产生已成为治疗AD的一种有吸引力的策略。这一建议直接阐述了A?42特异性抑制在突触可塑性和学习记忆中的机制和功能作用。这将大大促进以分泌酶为基础的阿尔茨海默病治疗的理解和发展。

项目成果

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YUEMING LI其他文献

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{{ truncateString('YUEMING LI', 18)}}的其他基金

Regulation of y-secretase activity by modulatory proteins
调节蛋白对 γ 分泌酶活性的调节
  • 批准号:
    10365920
  • 财政年份:
    2019
  • 资助金额:
    $ 57.46万
  • 项目类别:
Regulation of y-secretase activity by modulatory proteins
调节蛋白对 γ 分泌酶活性的调节
  • 批准号:
    10538600
  • 财政年份:
    2019
  • 资助金额:
    $ 57.46万
  • 项目类别:
Regulation of y-secretase activity by modulatory proteins
调节蛋白对 γ 分泌酶活性的调节
  • 批准号:
    10064120
  • 财政年份:
    2019
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and Synergy of gamma-Secretase Modulators
γ-分泌酶调节剂的机制和协同作用
  • 批准号:
    9270085
  • 财政年份:
    2016
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and Synergy of gamma-Secretase Modulators
γ-分泌酶调节剂的机制和协同作用
  • 批准号:
    9083397
  • 财政年份:
    2016
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and Synergy of gamma-Secretase Modulators
γ-分泌酶调节剂的机制和协同作用
  • 批准号:
    9918989
  • 财政年份:
    2016
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and therapy of AB-42-specific gamma-secretase
AB-42特异性γ-分泌酶的机制和治疗
  • 批准号:
    8260326
  • 财政年份:
    2011
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and therapy of AB-42-specific gamma-secretase
AB-42特异性γ-分泌酶的机制和治疗
  • 批准号:
    8663323
  • 财政年份:
    2011
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and therapy of AB-42-specific gamma-secretase
AB-42特异性γ-分泌酶的机制和治疗
  • 批准号:
    8856673
  • 财政年份:
    2011
  • 资助金额:
    $ 57.46万
  • 项目类别:
Mechanism and therapy of AB-42-specific gamma-secretase
AB-42特异性γ-分泌酶的机制和治疗
  • 批准号:
    8461609
  • 财政年份:
    2011
  • 资助金额:
    $ 57.46万
  • 项目类别:

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