Comparative Analysis of Transcriptome Profiles of Neural Stem/Progenitor Cells in Mouse and Zebrafish Brains after Amyloid-beta-42 Deposition

淀粉样蛋白-β-42 沉积后小鼠和斑马鱼大脑中神经干/祖细胞转录组谱的比较分析

• 批准号: 386893015
• 负责人: Dr. Caghan Kizil
• 金额: --
• 依托单位: Standort Dresden
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/386893015?language=en
• 关键词: Comparative; Analysis; Transcriptome; Profiles; Neural

In this proposal, we are aiming to compare the molecular response of neural stem/progenitor cells (NSPCs) of zebrafish and mouse after toxic aggregation amyloid-beta42, which is a major hallmark of Alzheimer's disease. We aim to find out the molecular differences between the NSPCs of zebrafish and mouse to hypothesize on a molecular framework of regenerative ability after neurodegeneration. We have recently found that in adult zebrafish brain, Amyloid-beta42 causes cell death, synaptic degeneration, inflammation and memory loss as in our brains. Interestingly, zebrafish also increased the proliferation of NSPCs, and produces more neurons even though Amyloid-beta42 toxicity. In our brains, we cannot activate our NSPCs to proliferate more, and produce more neurons, which is one of the major reasons why we cannot cope with neurodegenerative diseases by mounting a regeneration response, or activate a "plasticity cascade". Since our mammalian brains cannot fulfill such an increase in "plasticity", we hypothesized that we could learn from zebrafish how to coax our NSPCS to perform better in case of Alzheimer's disease. We are planning to do this by analyzing the gene expression in stem cells of zebrafish and mouse using already established Alzheimer disease models (our model in zebrafish, and a widely-used model in mouse). By performing protocols of deep sequencing of the gene expression and subsequent bioinformatics analyses, which are optimized in our laboratory, we anticipate to find out the genes that may make the difference between the "plasticity" capacities of zebrafish NSPCs and mammalian NSPCs. By pinpointing which genes must be activated or deactivated in disease conditions in order to fulfill a successful proliferation response of our brain stem cells, we will investigate the causes and consequences of Alzheimer's disease in the stem cells of our brain bettwe, and will also be able to design novel regenerative therapies based on our fundamental research.

在这项提议中，我们的目标是比较斑马鱼和小鼠的神经干/祖细胞（NSPCs）在毒性聚集淀粉样蛋白-β 42后的分子反应，淀粉样蛋白-β 42是阿尔茨海默病的主要标志。我们的目的是找出斑马鱼和小鼠的NSPCs之间的分子差异，以假设神经退行性变后再生能力的分子框架。我们最近发现，在成年斑马鱼大脑中，淀粉样蛋白-β 42导致细胞死亡，突触变性，炎症和记忆丧失，就像我们的大脑一样。有趣的是，斑马鱼也增加了NSPCs的增殖，并产生更多的神经元，即使淀粉样蛋白-β 42毒性。在我们的大脑中，我们不能激活我们的NSPCs增殖更多，并产生更多的神经元，这是我们不能通过安装再生反应或激活“可塑性级联”来科普神经退行性疾病的主要原因之一。由于我们的哺乳动物大脑无法实现这种“可塑性”的增加，我们假设我们可以从斑马鱼那里学习如何诱使我们的NSPCS在阿尔茨海默病的情况下表现得更好。我们计划通过使用已经建立的阿尔茨海默病模型（我们的斑马鱼模型和广泛使用的小鼠模型）分析斑马鱼和小鼠干细胞中的基因表达来做到这一点。通过对基因表达进行深度测序和随后的生物信息学分析，我们的实验室进行了优化，我们期望找到可能使斑马鱼NSPCs和哺乳动物NSPCs的“可塑性”能力之间存在差异的基因。通过精确定位哪些基因必须在疾病条件下激活或失活，以实现我们的脑干细胞的成功增殖反应，我们将调查阿尔茨海默病在我们大脑干细胞中的原因和后果，并且还将能够基于我们的基础研究设计新的再生疗法。