Systematic modeling and prediction of cell-type-specific and spatiotemporal crosstalk pathways in Alzheimer's Disease

摘要 阿尔茨海默病(AD)影响着全球5000多万人，但目前还没有明确的治疗方案 为病人着想。在过去的二十年里，AD的研究一直集中在以神经元为中心的生化过程上 这会导致突触缺陷和神经元退化。然而，最近临床试验的失败显然 证明我们目前对AD发病机制的理解存在知识差距，并呼吁进行研究，以导致 对不同类型脑细胞中的疾病途径进行公正和全面的了解。该项目旨在 结合计算系统生物学平台Single Cell解决这一重要而紧迫的问题 分辨率脑交互组(SCRBI)浏览器、3D人类阿尔茨海默氏症模型以及公开的 可通过NIH资助的AMP-AD门户网站获得多组学AD数据库。我们将扩展知识 SCRBI Explorer的基础，用于处理来自3D细胞模型的单细胞转录和多个组学图谱 以及人脑组织，它可以在多层神经元-胶质细胞和胶质细胞-胶质细胞串扰通路上检测到 通过配体-受体相互作用、细胞因子/趋化因子信号、细胞内信号活动和 转录激活。中心假设是多细胞系统生物学的组合使用 建模和3D人类AD细胞模型将识别AD特有的神经元-胶质细胞和胶质细胞-胶质细胞串扰 这将为药物重新定位提供新的治疗靶点。我们将通过以下方式验证这一假设 追求三个具体目标：1)开发多细胞串扰模型，以揭示改变的神经元-胶质细胞和 阿尔茨海默病中的胶质细胞-胶质细胞串扰通路，2)识别和验证AD特有的神经元-胶质细胞和胶质细胞-胶质细胞串扰 在3D人类AD细胞模型和人类AD脑细胞中丰富的通路，以及3)评估 应用AD三维人类神经细胞培养模型研究神经元-胶质细胞和神经胶质细胞串扰的治疗潜力。 这项建议的潜在影响很大，因为拟议的研究如果成功，将提供一个独特的 集成生物信息学工具无偏见地识别AD和AD中神经元-胶质细胞和胶质细胞-胶质细胞串扰通路 甚至是其他神经退行性疾病。更重要的是，它将提供新的治疗靶点，基于 阿尔茨海默病神经元-胶质细胞相互作用通路的改变及靶向细胞-细胞药物定位的新前景 阿尔茨海默病患者脑内的相互作用。

Abstract Alzheimer’s disease (AD) affects more than 50 million people worldwide but there is no clear therapeutic option for the patients. For last two decades, AD research has been focusing on a neuron-centric biochemical process that leads to synaptic deficits and neuronal degeneration. However, recent failures in clinical trials clearly demonstrate a gap in knowledge in our current understanding of AD pathogenesis and call for studies that lead to unbiased and holistic understanding of disease pathways in different types of brain cells. This project aims to tackle this important and urgent issue by combining a computational systems biology platform Single-Cell Resolution Brain Interactome (SCRBI) Explorer, 3D human Alzheimer’s-in-a-dish models, and the publicly available multiple-omics AD databases through NIH-funded AMP-AD portal. We will expand the knowledge base of SCRBI Explorer to handle single cell transcriptomic and multiple omics profiles from 3D cell models and human brain tissues, which can detect on multiple layers of neuron-glia and glia-glia crosstalk pathways via ligand-receptor interactions, cytokine/chemokine signaling, intracellular signaling activities, and transcriptional activation. The central hypothesis is that the combined use of multi-cellular systems biology modeling and 3D human AD cellular models will identify AD-specific neuron-glia and glia-glia crosstalk pathways, which would provide novel therapeutic targets for drug repositioning. We will test this hypothesis by pursuing three specific aims: 1) Develop a multi-cellular crosstalk model to uncover altered neuron-glia and glia-glia crosstalk pathways in AD, 2) identify and validate AD-specific neuron-glia and glia-glia crosstalk pathways that are enriched in 3D human AD cellular models and human AD brain cells, and 3) evaluate the therapeutic potential of neuron-glia and glia-glia crosstalk using 3D human neural cell culture models of AD. The potential impact of this proposal is high because the proposed study, if successful, will provide a unique integrated bioinformatics tool to unbiasedly identify neuron-glia and glia-glia crosstalk pathways in AD and even other neurodegenerative diseases. More importantly, it will provide novel therapeutic targets based on altered neuron-glia interaction pathways in AD and open up a new vista for drug repositioning targeting cell-cell interactions in the brain of AD patients.