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NEoC – NeuroEnergetics-on-Chip: Disease modeling of impaired brain glucose metabolism using human iPSC-derived neurovascular units (NVU)-on-chip systems

Project description

An organ-on-chip model for neurometabolic disturbances

The brain is highly energy-dependent and disruptions in this energy supply or its metabolic pathways can lead to various neurological conditions. In the brain, various cell types work together to maintain the integrity of the blood-brain barrier and ensure proper nutrient and waste exchange between the blood and the brain. This complex functional interaction known as the neurovascular unit (NVU) is critical in maintaining brain homeostasis. With the support of the Marie Skłodowska-Curie Actions programme, the NEoC project aims to develop an organ-on-chip model of the NVU using induced pluripotent stem cells. The team will focus on glucose transporter 1 deficiency syndrome and study the impact on the NVU.

Objective

Neurological conditions conquer the world; they are the leading cause of disability and second leading cause of death worldwide. Although there is growing evidence for the immense impact of disturbances in neurometabolism for overall brain function, only little is known about the underlying mechanisms (knowledge gap). Especially human insights are sparse due to a paucity of physiologically relevant model systems (research 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). Since GLUT1-DS is monogenic, it presents an excellent paradigm to study cellular and molecular consequences of disturbed neuroenergetics, even beyond the disease itself.
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.

Fields of science

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Coordinator

KAROLINSKA INSTITUTET
Net EU contribution
€ 206 887,68
Address
Nobels Vag 5
17177 Stockholm
Sweden

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Region
Östra Sverige Stockholm Stockholms län
Activity type
Higher or Secondary Education Establishments
Links
Total cost
No data