Using geroscience to understand and treat Alzheimer's disease

利用老年科学来理解和治疗阿尔茨海默病

• 批准号: 10432126
• 负责人: Pamela Anne Maher
• 金额: $ 76.61万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432126
• 关键词: Address; Affinity; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Animals; Bioinformatics; Biological Assay; Biology; Brain; Brain Pathology; CRISPR screen; Caenorhabditis elegans; Caloric Restriction; Cell Death; Cells; Chemicals; Chemistry; Clinic; Clinical Trials; Cognition; Dementia; Disease; Drug Industry; Drug Screening; Drug Targeting; Drug usage; Ensure; Gene Expression; Genetic Transcription; Geroscience; Goals; Hippocampus (Brain); Human; Individual; Investigational Drugs; Laboratories; Libraries; Longevity; Mammals; Memory impairment; Metabolism; Metformin; Modeling; Molecular; Molecular Target; Mus; Mutation; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathology; Pathway Analysis; Pathway interactions; Penetration; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Plasma; Population; Precipitation; Proteins; Proteomics; Protocols documentation; Public Health; Research Institute; Resources; Robotics; Safety; Scientist; Signal Pathway; Sirolimus; Source; Technology; Testing; Time; Toxic effect; Treatment Efficacy; Validation; Wild Type Mouse; Work; age related; aged; aging brain; anti aging; base; drug candidate; drug discovery; drug repurposing; effective intervention; effective therapy; familial Alzheimer disease; fly; human old age (65+); improved; innovation; man; metabolomics; mouse model; neuron loss; neurotoxicity; novel; novel strategies; novel therapeutics; prevent; programs; protective factors; screening; small molecule; tau Proteins; transcriptome sequencing; validation studies

Abstract: There are no effective treatments for age-dependent neurodegenerative conditions such as Alzheimer's disease (AD). To address this major public health crisis, the National Alzheimer's Project Act (NAPA) was passed to “find effective interventions to treat and prevent AD and related dementias by 2025.” To achieve this goal in 5 years one or more effective drugs are required, likely sourced from repurposed drugs that are the basis of this application. Dementias are diseases that occur with age. Therefore, aging must be incorporated into the drug target validation strategy to ensure that the target mechanism remains active in aged individuals and to facilitate an understanding of the interaction between aging and AD. The recognition of this fact led to the NOT-AG-18-051 initiative with one goal of “employing a lifespan approach to understand the mechanisms of protective and risk factors” for AD. In this application, we formally address the goals of both initiatives by integrating lifespan studies with an age-related phenotypic screening platform that has yielded compounds that extend lifespan (geroprotectors), one of which is now in AD clinical trials. During the last decade a novel phenotypic screening platform based upon 5 toxicities associated with the aged brain was used to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Surprisingly, these new synthetic compounds as well as their precursors slow aging in mice, keeping them younger at both the gene transcription and metabolomics levels and extend lifespan in other model organisms. The molecular target of one compound, J147, is identical to the target of a compound that extends lifespan in C. elegans. J147 has since been used in a 'chemical biology' approach to understand fundamental aspects of aging itself, for it engages essentially all of the known molecular pathways associated with the geroprotectors metformin and rapamycin as well as caloric restriction. Because of these new observations, we reasoned that by integrating lifespan studies in C. elegans with our novel phenotypic screening platform we could efficiently identify additional new aging pathways as well as AD drugs and drug targets. To accelerate the time needed to bring any discoveries to the clinic we will screen the ReFRAME library. This unique library consists of 12,000 compounds developed by the pharmaceutical industry, including nearly all that have ever been in man and those registered as investigational drug candidates. These drugs will initially be screened in the neurotoxicity assay used as our primary screen in previous drug discovery efforts. Positive hits will then be assayed for longevity in C. elegans. When necessary, target identification will be carried out as we have done in the past. Finally, pathway validation studies will be done in two very distinct mouse models of aging and dementia. This collaborative effort between three laboratories uses a new approach to understand the relationship between aging and dementia and the molecular pathways involved, with the likelihood of identifying new AD drugs.

摘要： 对于阿尔茨海默氏症等依赖年龄的神经退行性疾病，还没有有效的治疗方法 疾病(AD)。为了应对这一重大公共卫生危机，《国家阿尔茨海默氏症项目法》(NPA) 通过了“到2025年找到有效的干预措施来治疗和预防阿尔茨海默病和相关的痴呆”。要实现 这一目标在5年内需要一种或多种有效的药物，可能来自于 这个应用程序的基础。痴呆症是随着年龄增长而发生的疾病。因此，老化必须是 纳入药物靶标验证战略，以确保靶标机制在 并有助于了解老龄化和阿尔茨海默病之间的相互作用。认同感 这一事实导致了NOT-AG-18-051倡议，其一个目标是“使用生命周期的方法来理解 阿尔茨海默病的保护机制和危险因素。在本申请中，我们正式提出了以下目标 这两项倡议都是通过将寿命研究与与年龄相关的表型筛选平台相结合来实现的，该平台具有 产生了延长寿命的化合物(基因保护剂)，其中一种目前正在进行AD临床试验。 在过去的十年中，一个新的表型筛选平台，基于与 老化的大脑被用来识别在多种模型中具有治疗效果的化合物 神经变性和痴呆症。令人惊讶的是，这些新的合成化合物及其前体 延缓小鼠的衰老，使它们在基因转录和代谢组学水平上保持年轻并延长 其他模式生物的寿命。一种化合物J147的分子靶标与一种 能延长线虫寿命的化合物。自那以后，J147被用在一种“化学生物学”的方法中 了解衰老本身的基本方面，因为它基本上涉及所有已知的分子 与促性腺激素保护剂二甲双胍和雷帕霉素以及热量限制相关的通路。因为 在这些新的观察中，我们认为通过将线虫寿命研究与我们的小说结合起来 表型筛选平台，我们可以有效地识别其他新的衰老途径以及AD 毒品和毒品目标。为了加快将任何发现带到诊所所需的时间，我们将筛选 重定框库。这个独特的文库由该制药公司开发的12,000种化合物组成 工业，包括几乎所有曾经在人类身上出现过的药物和那些注册为研究药物的药物 候选人。这些药物最初将在作为我们主要筛查的神经毒性试验中进行筛选 之前的药物发现工作。然后，将对线虫的寿命进行阳性检测。什么时候 必要时，将像我们过去所做的那样进行目标识别。最后，路径验证 研究将在两种截然不同的衰老和痴呆症小鼠模型上进行。这一合作努力 三个实验室之间使用了一种新的方法来了解衰老和痴呆症之间的关系 以及涉及的分子途径，以及识别新的AD药物的可能性。