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

点击翻译按钮获取中文摘要

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.