The Alzheimer's Disease Resiliome: Pathway Analysis and Drug Discovery.

阿尔茨海默病弹性组：通路分析和药物发现。

基本信息

批准号：
10649411
负责人：
Winston Alexander Hide
金额：
$ 65.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649411
关键词：
3-Dimensional AD transgenic mice Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Amyloid Amyloid Beta A4 Precursor Protein Amyloid beta-42 Amyloid beta-Protein Amyloid deposition Autopsy Biological Models Brain Cell Culture Techniques Cell model Cognition Cognitive Cognitive deficits Collaborations Combined Modality Therapy Compensation Data Data Set Dementia Deposition Drug Combinations Drug Screening Drug usage Elderly FDA approved Family Gene Cluster Gene Expression Genes Genetic Goals Human Impaired cognition Incidence Individual Intervention Link Literature Modeling Molecular Mus Mutant Strains Mice National Institute of Mental Health Natural Resistance Nerve Degeneration Neurofibrillary Tangles Neuroglia Neurons Pathogenicity Pathology Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Proxy Resistance Senile Plaques Sepsis Series Symptoms Synapses System Techniques Testing Therapeutic Intervention Transgenic Organisms aging population clinical application clinical development clinically relevant cohort combinatorial dosage drug candidate drug discovery drug repurposing drug testing drug-sensitive effective intervention experimental study genome analysis genome sequencing genome wide association study human subject innovation insight mouse model neural neurofibrillary tangle formation neuroinflammation neuron loss neuropathology neuroprotection novel novel therapeutics prevent promote resilience resilience screening targeted treatment tau Proteins tau aggregation technology validation tool transcriptome whole genome

3-Dimensional AD transgenic mice Address Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Amyloid Amyloid Beta A4 Precursor Protein Amyloid beta-42 Amyloid beta-Protein Amyloid deposition Autopsy Biological Models Brain Cell Culture Techniques Cell model Cognition Cognitive Cognitive deficits Collaborations Combined Modality Therapy Compensation Data Data Set Dementia Deposition Drug Combinations Drug Screening Drug usage Elderly FDA approved Family Gene Cluster Gene Expression Genes Genetic Goals Human Impaired cognition Incidence Individual Intervention Link Literature Modeling Molecular Mus Mutant Strains Mice National Institute of Mental Health Natural Resistance Nerve Degeneration Neurofibrillary Tangles Neuroglia Neurons Pathogenicity Pathology Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Proxy Resistance Senile Plaques Sepsis Series Symptoms Synapses System Techniques Testing Therapeutic Intervention Transgenic Organisms aging population clinical application clinical development clinically relevant cohort combinatorial dosage drug candidate drug discovery drug repurposing drug testing drug-sensitive effective intervention experimental study genome analysis genome sequencing genome wide association study human subject innovation insight mouse model neural neurofibrillary tangle formation neuroinflammation neuron loss neuropathology neuroprotection novel novel therapeutics prevent promote resilience resilience screening targeted treatment tau Proteins tau aggregation technology validation tool transcriptome whole genome

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项目摘要

There are no effective drugs to prevent Alzheimer’s disease (AD). We seek to prevent onset or progression of AD by discovering and enhancing the activity of naturally occurring pathways that prevent its occurrence. This natural resilience is significant because it is the only known manner in which Alzheimer’s appears to be controlled. Here, we exploit the fact that a proportion of the aging population appear to remain cognitively intact while controlling or compensating AD related Tau pathology and enjoy a relative natural resistance to cognitive impairment or diagnosis of AD. Using whole genome sequencing (WGS) and transcriptome analysis of a naturally AD-resilient population, we will identify novel drug-sensitive resilience associated (RA) pathways in AD. We will implement a novel, validated technology, the Pathway Drug Network (PDN), constructed from human gene expression data enriched in drug–pathway–gene clusters, to identify drugs that enhance RA pathways. First round screening of the PDN-predicted single or combinations of leads will be tested in our innovative 3D human neural cell culture models of AD, which recapitulate various pathogenic stages of AD including Ab deposition (Ab plaque), Ab-driven tau pathology (neurofibrillary tangles (NFTs), and neuroinflammation and neurodegeneration. Validated leads will then be scored in transgenic AD mouse models for reduction of synaptic loss and cognitive integrity. The approach will establish the basis for a therapeutic intervention that can prevent or reduce cognitive decline related to AD. Intellectual merit: This project will significantly advance the understanding of neuroprotection in aging adult human brains while providing novel insights into the relationships between control of AD related pathology and loss of cognition. Broader impact: AD increasingly affects the aging population and there is no effective intervention. Reduction of its incidence will be of major significance. If successful, the project will allow development of clinical application of novel drugs or repurposed FDA approved drugs while creating a powerful new paradigm for developing successful AD drug combinations. Aim1: Using network analytical techniques, we will generate a molecular systems definition of RA pathways using pathways, genes and network modules from whole genome sequencing data and literature, and post mortem brain transcriptomes that show resilient high or low plaque/tangle, low AD symptoms, but high cognitive scores. Aim 2: Compare RA pathways within PDN to predict drug/pathway combinations that confer resilience. A series of drug-repurposing screens will optimise lists of ranked drugs/combinations and pathway activity. Selected combinations will be validated in multiple 3D human neural cell culture models of AD that mimic various pathogenic stages of AD for their impact on AD pathogenic markers. Aim 3: Validate using proxies of cognition in an AD transgenic APP mouse model. Score for the ability to confer resilience and neuroprotection in AD transgenic mouse models for either Ab deposition, synaptic/cognitive deficits and/or neuroinflammation.

没有有效的药物可以预防阿尔茨海默氏病（AD）。我们试图防止发作或进展通过发现和增强自然发生的途径的活动，以防止其发生。这自然弹性很重要，因为它是阿尔茨海默氏症似乎是唯一已知的方式受控。在这里，我们探讨了一个事实，即一定比例的老龄化人口似乎保持不变在控制或补偿与AD相关的TAU病理学并享有对认知的相对自然抗性的同时 AD的障碍或诊断。使用全基因组测序（WGS）和A的转录组分析自然的广告种群，我们将确定与药物敏感的新型韧性相关（RA）途径广告。我们将实施一种新颖的，经过验证的技术，途径药物网络（PDN），该技术由人类基因表达数据富含药物 - 同步 - 基因簇，以识别增强RA的药物途径。将在我们的第一轮筛选PDN预测的单一或铅组合中进行测试创新的3D人类神经元细胞培养AD的培养模型，该模型概括了AD的各种致病阶段包括AB沉积（AB斑块），AB驱动的TAU病理学（神经纤维缠结（NFTS）和神经炎症和神经变性。然后，经过验证的线索将在转基因AD鼠标中评分降低突触损失和认知完整性的模型。该方法将建立一个基础可以预防或减少与AD相关的认知下降的治疗干预措施。智力优点：这个项目将显着提高成年人大脑衰老的神经保护的理解提供新的见解，以了解与AD相关病理控制与认知丧失之间的关系之间的关系。更广泛的影响：广告越来越多地影响人口老龄化，没有有效的干预。减少它的事件将具有重要意义。如果成功，该项目将允许开发临床在创建强大的新范式的同时，应用新型药物或重新使用的FDA批准的药物开发成功的AD药物组合。 AIM1：使用网络分析技术，我们将生成一个分子系统使用整个途径，基因和网络模块的RA途径定义基因组测序数据和文献，以及验尸脑转录组，显示出弹性的高或低斑块/缠结，低广告符号，但认知得分很高。目标2：将PDN中的RA途径与预测会议弹性的药物/途径组合。一系列药物替代屏幕将优化排名药物/组合和途径活动的清单。选定的组合将在多个3D中进行验证 AD的人类神经细胞培养模型模仿AD的各种致病阶段，以影响AD 致病标记。 AIM 3：在AD转基因应用鼠标模型中使用认知代理进行验证。分数为了在AB沉积中赋予AD转基因小鼠模型中赋予弹性和神经保护的能力，突触/认知缺陷和/或神经炎症。