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

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病 (AD)，我们力求预防阿尔茨海默病的发作或进展。通过发现和增强自然发生途径的活性来预防 AD 的发生。自然恢复力很重要，因为这是唯一已知的阿尔茨海默病的治疗方式在这里，我们利用了这样一个事实：一部分老年人口的认知能力似乎保持完好。同时控制或补偿AD相关的Tau蛋白病理并享有相对自然的认知抵抗力使用全基因组测序 (WGS) 和转录组分析来诊断 AD。自然 AD 弹性人群，我们将确定新的药物敏感弹性相关 (RA) 途径 AD。我们将实施一项经过验证的新颖技术，即 Pathway Drug Network (PDN)。富含药物-途径-基因簇的人类基因表达数据，以确定增强 RA 的药物 PDN 预测的单一或组合线索的第一轮筛选将在我们的测试中进行测试。创新的 AD 3D 人类神经细胞培养模型，概括了 AD 的各个致病阶段包括 Ab 沉积（Ab 斑块）、Ab 驱动的 tau 病理学（神经原纤维缠结 (NFT) 和然后将对转基因 AD 小鼠的神经炎症和神经变性进行评分。该方法将为减少突触损失和认知完整性的模型奠定基础。可以预防或减少与 AD 相关的认知能力下降的治疗干预：这。该项目将显着增进对衰老成人大脑神经保护的理解，同时为 AD 相关病理控制与认知丧失之间的关系提供了新颖的见解。更广泛的影响：AD 对老龄化人口的影响越来越大，并且没有有效的干预措施。如果成功，该项目将有助于临床开发。应用新药或重新利用 FDA 批准的药物，同时创建一个强大的新范例开发成功的 AD 药物组合目标 1：使用网络分析技术，我们将生成一个使用整体的通路、基因和网络模块对 RA 通路进行分子系统定义基因组测序数据和文献，以及死后大脑转录组显示弹性高或低斑块/缠结，AD 症状低，但认知得分高目标 2：比较 PDN 内的 RA 通路。预测赋予弹性的药物/途径组合一系列药物再利用筛选将得到优化。排名药物/组合和途径活性的列表将在多个 3D 中进行验证。 AD 的人类神经细胞培养模型，模拟 AD 的各个致病阶段，了解它们对 AD 的影响目标 3：在 AD 转基因 APP 小鼠模型中使用认知代理进行验证。为 AD 转基因小鼠模型赋予抗体沉积的恢复能力和神经保护能力，突触/认知缺陷和/或神经炎症。