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: 8202120
• 负责人: YUEMING LI
• 金额: $ 57.46万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8202120
• 关键词: Address; Adverse effects; Affect; Allosteric Site; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein Precursor; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Proteins; Biochemical; Biological; Biological Models; Biological Process; Biology; Cell model; Cellular Assay; Cellular biology; Characteristics; Chemicals; Cleaved cell; Clinical Trials; Cognition; Coumarins; Development; Drug Delivery Systems; Exhibits; Generations; Goals; In Vitro; Individual; Investigation; Kidney; Knock-in Mouse; Label; Lead; Learning; Left; Length; Mediating; Memory; Metabolism; Molecular Mechanisms of Action; Molecular Probes; Monitor; Monophenol Monooxygenase; Mus; Neurons; Neuropathogenesis; Pathogenesis; Pathway interactions; Peptides; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Play; Process; Production; Property; Protein Overexpression; Proteins; Proteomics; Regulation; Research Personnel; Role; Series; Skin Neoplasms; Skin Pigmentation; Specificity; Synaptic plasticity; System; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; alpha benzopyrone; amyloid pathology; amyloid precursor protein processing; analog; base; efficacy testing; gamma secretase; in vivo; inhibitor/antagonist; innovation; lysosomal proteins; melanocyte; mouse model; mutant; neuron development; notch protein; novel; prevent; protein transport; secretase; synaptic function; therapeutic development; tumor progression; tumorigenesis

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。