Project description
Brain microvasculature might mediate a sickeningly sweet response in neurons
Glucose oxidation releases ATP, the energy that fuels cell activities. Critical for cellular functions, glucose homeostasis is disrupted in disease conditions like diabetes. Increasing evidence suggests that high levels of blood glucose (hyperglycaemia) disrupt neural cell function and may be involved in neurodegenerative diseases. The neurovascular unit (NVU) is command and control for the brain's supply of and demand for oxygen and nutrients. It includes the blood-brain barrier of endothelial cells and tight junctions of the blood vessels as well as nervous system cells. SweetBrain will tackle a number of important issues, such as the lack of human-relevant models (developing NVU on a Chip), better understanding the cellular interactions in complex human physiological systems (using the NVU Chip for this) and to identify how and why high glucose levels (not necessarily related to diabetes) make people three times more prone to develop neurodegenerative disease.
Objective
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.
Fields of science (EuroSciVoc)
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This project's classification has been validated by the project's team.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
This project's classification has been validated by the project's team.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Call for proposal
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(opens in new window) ERC-2019-STG
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69978 Tel Aviv
Israel
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