NEoC – NeuroEnergetics-on-Chip: Disease modeling of impaired brain glucose metabolism using patient-specific iPSC-derived microphysiological models of the neurovascular unit

NEoC â NeuroEnergetics-on-Chip：使用患者特异性 iPSC 衍生的神经血管单元微生理模型对大脑葡萄糖代谢受损进行疾病建模

• 批准号: 525882861
• 负责人: Dr. Julia Rogal
• 金额: --
• 依托单位: KTH - Royal Institute of Technology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/525882861?language=en
• 关键词: NEoC; NeuroEnergetics; Chip; Disease; modeling

Neurological conditions conquer the world; they are the leading cause of disability and second leading cause of death worldwide. Globally, in 2019, nearly one billion people were affected by mental, neurological and substance use disorders, accounting for 25% of disability-adjusted life years (DALYs). Neurological conditions appear all around the world in every age group, gender, nationality, and socioeconomic class. Adding to the immeasurable burden on everyday lives of patients and their dependents, brain disorders are a socioeconomic strain with annual costs of ~800 billion € in Europe alone. Yet, despite increasing incidences of neurodegenerative and neuropsychiatric disorders, drug development proved cumbersome to the point that many pharmaceutical companies stepped back from CNS research. Many drug candidates fail at the translation to the clinic pointing to a shortage of predictive model systems. Especially human insights are sparse due to a paucity of physiologically relevant model systems (research gap). One aspect, which is increasingly identified as key contributor to a vast range of neurological disorders, are disturbances of energy metabolism. And yet, relatively little attention was paid to our ‘neuroenergetics’ in the past (knowledge gap). To address these challenges, within the scope of the NeuroEnergetics-on-Chip (NEoC) project, I am proposing the development of a novel, human iPSC-based organ-on-chip model of the neurovascular unit (NVU) that integrates all neurometabolically active NVU cell types and specifically enables the inspection of neurometabolic coupling mechanisms. To categorically cast light onto the mechanisms behind impaired metabolism of glucose (the brain’s principal energy supplier), I will build an NVU-on-Chip disease model of glucose transporter 1 deficiency syndrome (GLUT1-DS). Its monogenic nature makes GLUT1-DS an excellent paradigm to study not only the disease itself but also general cellular and/or molecular consequences of energy failure. For implementation of the NEoC project, I will i) generate all neurometabolically relevant NVU cell types (endothelial cells, perivascular cells, astrocytes, microglia and neurons) from human iPSC lines derived from GLUT1-DS patients, ii) develop a novel NVU microfluidic platform addressing the shortcomings of existing NVU-on-Chip systems, and iii) build GLUT1-DS-NVU-on-Chip models to specifically study perturbations in energy metabolism, blood-brain barrier integrity and neuroinflammation as a consequence of GLUT1-DS in vitro. The NEoC project will provide novel knowledge on the underlying mechanisms and pathophysiology of GLUT1-DS, and thereby not only benefit those afflicted by the orphan disease but impact our understanding of a variety of other CNS and metabolically linked disorders.

神经系统疾病征服世界;它们是世界范围内残疾的主要原因和死亡的第二大原因。在全球范围内，2019年，近10亿人受到精神、神经和物质使用障碍的影响，占残疾调整生命年（DSDs）的25%。神经系统疾病出现在世界各地的每个年龄组，性别，国籍和社会经济阶层。除了给患者及其家属的日常生活带来不可估量的负担外，脑部疾病是一种社会经济压力，仅在欧洲每年的成本就高达8000亿欧元。然而，尽管神经退行性疾病和神经精神疾病的发病率不断增加，但药物开发被证明是繁琐的，以至于许多制药公司退出了CNS研究。许多候选药物在临床应用中失败，这表明预测模型系统的短缺。特别是人类的见解是稀疏的，由于缺乏生理相关的模型系统（研究差距）。一个方面，这是越来越多地确定为一个广泛的神经系统疾病的关键贡献者，是能量代谢紊乱。然而，在过去，我们对“神经能量学”的关注相对较少（知识差距）。为了应对这些挑战，在NeuroEnergetics-on-Chip（NEoC）项目的范围内，我提议开发一种新型的基于人类iPSC的神经血管单元（NVU）器官芯片模型，该模型集成了所有神经代谢活性NVU细胞类型，并特别能够检查神经代谢偶联机制。为了明确揭示葡萄糖代谢受损（大脑的主要能量供应者）背后的机制，我将建立葡萄糖转运蛋白1缺乏综合征（GLUT 1-DS）的NVU芯片疾病模型。它的单基因性质使GLUT 1-DS成为研究疾病本身以及能量衰竭的一般细胞和/或分子后果的极好范例。为了实施NEoC项目，我将i）生成所有神经代谢相关的NVU细胞类型（内皮细胞、血管周围细胞、星形胶质细胞、小胶质细胞和神经元），ii）开发新的NVU微流体平台，解决现有NVU芯片系统的缺点，和iii）构建GLUT 1-DS-NVU芯片模型以专门研究能量代谢的扰动，血脑屏障完整性和神经炎症作为体外GLUT 1-DS的结果。NEoC项目将提供关于GLUT 1-DS的潜在机制和病理生理学的新知识，从而不仅使那些患有孤儿病的人受益，而且影响我们对各种其他CNS和代谢相关疾病的理解。