iPSC Macrophages/microglia and genome-wide CRISPR/Cas9 screening to investigate lipid accumulation in the pathophysiology of Alzheimer's Disease
iPSC 巨噬细胞/小胶质细胞和全基因组 CRISPR/Cas9 筛选研究阿尔茨海默病病理生理学中的脂质积累
基本信息
- 批准号:2886802
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:英国
- 项目类别:Studentship
- 财政年份:2023
- 资助国家:英国
- 起止时间:2023 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
BackgroundLipid accumulation in the cell cytoplasm of Alzheimer's brains was observed in the earliest descriptions of the disease. However, the vast majority of biomedical research in Alzheimer's disease (AD) has focused on the two gross histopathological targets of amyloid plaques and neurofibrillary tangles. The result of this research has been over 200 clinical trials focusing on these two targets that failed to generate an effective therapy. There are several reasons for this failure; among these are the poor understanding of the fundamental pathophysiology of Alzheimer's disease and the poor choice of disease models to more faithfully mimic the human cells most associated with AD pathology.Recently, GWAS studies have identified lipid metabolism as an important pathway in Alzheimer's disease (Jansen et al., 2019), with GWAS hits, such as Trem2 and ApoE, involved in lipid sensing and processing, in addition to regulation of inflammatory processes. A greater understanding of lipid regulation, and in particular of neuroinflammation, would be fundamental to understanding the pathophysiology of AD. Macrophages and microglia containing accumulations of lipids upon inflammation have been described (Nadjar, 2018). Lipid droplets, consisting of neutral lipids such as triacylglycerols and diacylglycerols, have been associated with inflammation and cytokine storage, but also with homeostatic functions, such as storage of fatty acids that could support phagocytosis and proper mitochondria functioning.All these studies strongly evidence that fatty acids can modulate microglial phagocytic activity. More studies are needed however to understand the mechanisms by which microglia interact with fatty acids and how they can shift microglia from one phenotype/function to another. Moreover, we still need to address the net outcome of these functional shifts for brain homeostasis, since depending on the context, increasing microglial phagocytosis might be beneficial (e.g. clearance of A plaques) or detrimental (e.g. phagocytosis of functional synapses).Research DesignThis project will investigate whether altering microglia lipid accumulation can improve microglial functions in human cell models. By modelling the disease effectively using patient-derived iPSC differentiated into microglia, targets affecting lipid accumulation will be identified through genome-wide CRISPR/Cas9 screening. Firstly, a robust assay for lipid droplet formation in human iPSC-derived microglia will be developed and comparisons between disease and isogenic lines explored. A genome-wide CRISPR/Cas9 screen will then be performed to identify important genes involved in lipid accumulation and potential targets for therapeutic validation. Further assessments will then be made of the consequences of lipid droplet formation and modulation by compounds on phagocytosis, ROS and cytokine production. Finally, the effect of lipid droplet modulation on complex co-culture models including neurons and astrocytes will be investigated.ImplicationUsing human iPSC-derived microglia will enable more faithful modelling of the cells associated with the disease, and by investigating this unexplored role of microglial lipid accumulation in the pathophysiology of AD, we aim to identify new targets that can be explored as potential new strategies for therapeutic intervention in Alzheimer's disease.ReferencesJansen, I. E. et al. 2019. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nature Genetics 51(3), pp. 404-413. doi: 10.1038/s41588-018-0311-9Nadjar, A. 2018. Role of metabolic programming in the modulation of microglia phagocytosis by lipids. Prostaglandins Leukot Essent Fatty Acids 135, pp. 63-73. doi: 10.1016/j.plefa.2018.07.006
研究背景在阿尔茨海默病的最早描述中,就观察到了这种疾病的细胞质中的脂质积累。然而,阿尔茨海默病(AD)的绝大多数生物医学研究都集中在淀粉样斑块和神经元缠结这两个大体的组织病理学靶点上。这项研究的结果是超过200项临床试验集中在这两个目标,未能产生有效的治疗。这种失败有几个原因;其中包括对阿尔茨海默病的基本病理生理学了解不足,以及疾病模型的选择不佳,无法更忠实地模拟与AD病理最相关的人类细胞。最近,GWAS研究已确定脂质代谢是阿尔茨海默病的一个重要途径(Jansen等人,2019年),GWAS命中,如Trem 2和ApoE,参与脂质传感和加工,除了炎症过程的调节。更好地了解脂质调节,特别是神经炎症,将是了解AD的病理生理学的基础。已经描述了炎症时含有脂质积聚的大胶质细胞和小胶质细胞(Nadjar,2018)。由中性脂质如甘油三脂和甘油二脂组成的脂滴不仅与炎症和细胞因子储存有关,而且还与体内平衡功能有关,如储存脂肪酸以支持吞噬作用和线粒体正常功能,所有这些研究都有力地证明了脂肪酸可以调节小胶质细胞的吞噬活性。然而,需要更多的研究来了解小胶质细胞与脂肪酸相互作用的机制,以及它们如何将小胶质细胞从一种表型/功能转变为另一种。此外,我们仍然需要解决的净结果,这些功能的变化,脑内稳态,因为根据上下文,增加小胶质细胞的吞噬作用可能是有益的(如A斑块的清除)或有害的(如功能性突触的吞噬作用)。通过使用分化为小胶质细胞的患者来源的iPSC有效地模拟疾病,将通过全基因组CRISPR/Cas9筛选来识别影响脂质积累的靶标。首先,将开发用于人iPSC衍生的小胶质细胞中脂滴形成的稳健测定,并探索疾病和等基因系之间的比较。然后将进行全基因组CRISPR/Cas9筛选,以确定参与脂质积累的重要基因和治疗验证的潜在靶点。然后将进一步评估脂滴形成的后果以及化合物对吞噬作用、ROS和细胞因子产生的调节。最后,将研究脂滴调节对包括神经元和星形胶质细胞在内的复杂共培养模型的影响。使用人iPSC衍生的小胶质细胞将能够更忠实地模拟与疾病相关的细胞,并通过研究小胶质细胞脂质积累在AD病理生理学中的未探索作用,我们的目标是确定新的靶点,这些靶点可以作为阿尔茨海默病治疗干预的潜在新策略进行探索。E.等,2019年。全基因组荟萃分析确定了影响阿尔茨海默病风险的新位点和功能途径Nature Genetics 51(3),pp. 404-413. doi:10.1038/s41588-018-0311-9Nadjar,A. 2018.代谢程序在脂质调节小胶质细胞吞噬作用中的作用。前列腺素Leukot Essent Fatty Acids 135,pp. 63-73. doi:10.1016/j.plefa.2018.07.006
项目成果
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其他文献
吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
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LiDAR Implementations for Autonomous Vehicle Applications
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2021 - 期刊:
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
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