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
- 来源:
- 关键词:AddressAdverse effectsAffectAllosteric SiteAlzheimer&aposs DiseaseAmino AcidsAmyloid beta-Protein PrecursorAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryBindingBinding ProteinsBiochemicalBiologicalBiological ModelsBiological ProcessBiologyCell modelCellular AssayCellular biologyCharacteristicsChemicalsCleaved cellClinical TrialsCognitionCoumarinsDevelopmentDrug Delivery SystemsExhibitsGenerationsGoalsIn VitroIndividualInvestigationKidneyKnock-in MouseLabelLeadLearningLeftLengthMediatingMemoryMetabolismMolecular Mechanisms of ActionMolecular ProbesMonitorMonophenol MonooxygenaseMusNeuronsNeuropathogenesisPathogenesisPathway interactionsPeptidesPharmaceutical PreparationsPhase III Clinical TrialsPhysiologicalPlayProcessProductionPropertyProtein OverexpressionProteinsProteomicsRegulationResearch PersonnelRoleSeriesSkin NeoplasmsSkin PigmentationSpecificitySynaptic plasticitySystemTertiary Protein StructureTestingTherapeuticTherapeutic EffectTreatment Efficacyalpha benzopyroneamyloid pathologyamyloid precursor protein processinganalogbaseefficacy testinggamma secretasein vivoinhibitor/antagonistinnovationlysosomal proteinsmelanocytemouse modelmutantneuron developmentnotch proteinnovelpreventprotein transportsecretasesynaptic functiontherapeutic developmenttumor progressiontumorigenesis
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
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 }}
YUEMING LI其他文献
YUEMING LI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('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:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 57.46万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 57.46万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 57.46万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 57.46万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
- 批准号:
RGPIN-2018-04753 - 财政年份:2022
- 资助金额:
$ 57.46万 - 项目类别:
Discovery Grants Program - Individual