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A new perspective on the metabolic pathway to neuronal dysfunction: Using organs on a chip to elucidate the role of the brain microvasculature

Descrizione del progetto

La microvascolarizzazione cerebrale potrebbe mediare una risposta disgustosamente dolce nei neuroni

L’ossidazione del glucosio rilascia ATP, l’energia che alimenta le attività cellulari. Fondamentale per le funzioni cellulari, l’omeostasi del glucosio è alterata in condizioni patologiche quali il diabete. Prove crescenti suggeriscono che alti livelli di glucosio nel sangue (iperglicemia) disturbano la funzione delle cellule neurali e potrebbero essere implicati in malattie neurodegenerative. L’unità neurovascolare (NVU) rappresenta il comando e il controllo della fornitura e della domanda di ossigeno e nutrienti da parte del cervello. Essa include la barriera emato-encefalica delle cellule endoteliali e le giunzioni strette dei vasi sanguigni nonché le cellule del sistema nervoso. Il progetto SweetBrain affronterà una serie di questioni importanti, quali la mancanza di modelli rilevanti per l’uomo (sviluppo di NVU su chip), una migliore comprensione delle interazioni cellulari nei complessi sistemi fisiologici umani (uso di chip NVU per questo) e l’identificazione di come e perché livelli elevati di glucosio (non necessariamente correlati al diabete) rendono le persone tre volte più inclini a sviluppare malattie neurodegenerative.

Obiettivo

Despite decades of research, the underpinnings of central nervous system (CNS) diseases and clear pathways to effective treatment remain elusive, mainly because of a scarcity of adequate models and methods with the capacity to elucidate human brain physiology. Recent studies suggest that high glucose levels are correlated with neuronal dysfunction and neurodegeneration, yet very little is known about the mechanisms of this relationship. Research in this vein has focused primarily on direct metabolic interactions between neurons and astrocytes, ignoring other cell populations in the neurovascular unit (NVU) that might have a meaningful role. My recent research revealed that the brain vasculature—the ‘gatekeeper’ through which all metabolites must pass to reach the neurons—has direct metabolic coupling with the neurons. Drawing from these observations, I adopt a previously unconsidered perspective and propose that the vasculature drives the neurodegenerative effects of hyperglycemia. Specifically, I hypothesize that high glucose levels change the metabolic function of the brain vasculature, thereby altering the direct endothelium-neuronal crosstalk and triggering neuronal dysfunction. To investigate this hypothesis, I will develop cutting-edge Organ-on-a-Chip (OoC) technology that overcomes the limitations of modeling NVU functionality and cell-cell interactions. Specifically, I will:
(1) establish a human-relevant NVU-OoC model for metabolic and functional interactions, in which different cell types grow separately while remaining metabolically and functionally coupled;
(2) identify the major metabolic and functional interactions in the human NVU at homeostasis and under diabetic conditions; and subsequently (3) target the vasculature communications to diminish neuronal dysfunction. This research has the potential to revolutionize the study of CNS disease, pointing to an unexplored pathway to a cure, and illuminating fundamental questions regarding brain metabolism.

Meccanismo di finanziamento

ERC-STG - Starting Grant

Istituzione ospitante

TEL AVIV UNIVERSITY
Contribution nette de l'UE
€ 1 487 438,00
Indirizzo
RAMAT AVIV
69978 Tel Aviv
Israele

Mostra sulla mappa

Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 487 438,00

Beneficiari (1)