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

神经系统疾病征服世界；它们是世界范围内导致残疾的首要原因和第二大死亡原因。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，占残疾调整寿命年(DALY)的25%。神经系统疾病出现在世界各地的各个年龄段、性别、国籍和社会经济阶层。脑部疾病给患者及其家属的日常生活增加了无法估量的负担，仅在欧洲就造成了每年约8000亿欧元的社会经济压力。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，但事实证明，药物开发非常繁琐，以至于许多制药公司放弃了对中枢神经系统的研究。许多候选药物在转化为临床时失败，原因是缺乏预测模型系统。特别是，由于缺乏与生理相关的模型系统(研究缺口)，人类的洞察力很稀少。其中一个方面，越来越多地被认为是导致一系列神经疾病的关键因素，这是能量代谢障碍。然而，在过去，我们的‘神经能量学’相对较少受到关注(知识鸿沟)。为了应对这些挑战，在神经能量学芯片(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，该模型整合了所有神经代谢活跃的NVU细胞类型，并特别能够检查神经代谢耦合机制。为了彻底阐明葡萄糖(大脑的主要能量供应者)代谢受损背后的机制，我将建立一个葡萄糖转运蛋白1缺乏综合症(GLUT1-DS)的NVU-on-Chip疾病模型。它的单基因特性使GLUT1-DS不仅是研究疾病本身，而且研究能量衰竭的一般细胞和/或分子后果的极佳范例。为了实施NEoC项目，我将：i)从GLUT1-DS患者的人IPSC系中培养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)开发一个新颖的NVU微流控平台，解决现有NVU芯片系统的缺点；以及iii)建立GLUT1-DS-NVU-on-Chip模型，专门研究GLUT1-DS体外导致的能量代谢、血脑屏障完整性和神经炎症方面的扰动。NEoC项目将为GLUT1-DS的潜在机制和病理生理学提供新的知识，从而不仅使那些受到孤儿疾病困扰的人受益，而且影响我们对各种其他中枢神经系统和代谢相关疾病的理解。

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.