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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

Periodic Reporting for period 2 - SweetBrain (A new perspective on the metabolic pathway to neuronal dysfunction: Using organs on a chip to elucidate the role of the brain microvasculature)

Reporting period: 2022-03-01 to 2023-08-31

The main goal of this project is to identify how sugar leads to neurodegeneration. This has a major impact on society, as in recent years it was observed that there is a link between high sugar levels and neurodegeneration.
Moreover, as modern societies show huge sugar consumption, this project is especially important for reducing the health risks of sugar consumption.
To achieve this, we use state of the art-human relevant models, know as Organs-on-a-Chip, to decipher the lead of how sugar leads to neurodegeneration.

The main objectives are:
Aim 1. Establish a human-relevant NVU model for metabolic and functional interactions.
Aim 2. Identify the major metabolic and functional interactions in the human NVU at homeostasis and under diabetic conditions.
Aim 3. Target the vasculature–neuron communications to diminish neuronal dysfunction.

This work tackles major challenges faced by researchers studying the physiology of complex human systems, and specifically the relationship between blood glucose concentrations and neuronal dysfunction. This project has different levels of risk, where the last aim—effectively, identifying an avenue to treating neuronal degeneration—is particularly ambitious and bold. However, the project has been carefully designed in such a way that each step is feasible and has the potential to provide groundbreaking results. Specifically, successfully accomplishing the aims outlined above will provide a new human-relevant model of the NVU; it will map the cell-cell metabolic interactions in the NVU; and it will pinpoint the components of vasculature-neuronal communication that are significant for neuron functionality. Moreover, it will provide new insights regarding the effects of elevated glucose levels on the different compartments of the NVU, and specifically on the vasculature-neuronal communication. Notably, it will shed light on fundamental open questions regarding the effects of insulin and insulin resistance on the NVU. Most importantly, it will change the current dogma, in which the major metabolic effects of glucose on neuronal functionality are thought to be embedded in neuronal-astrocyte interactions. Instead, it will establish a new dogma focusing on vasculature-neuronal communication, thereby creating new research avenues and new therapeutic approaches that address neuronal dysfunction.
In the last period of research, we focused on the following aims:
Platform development: – we developed a “Smart”-Organ-on-a-Chip which allows measuring the vascular functionality with spatial resolution. This work was published in Lab Chip (Renous, Noa, et al. "Spatial trans-epithelial electrical resistance (S-TEER) integrated in organs-on-chips." Lab on a Chip 22.1 (2022): 71-79, back cover)). In addition, we developed a modular chip that can transform a culture well into a chip, which saves time, money and it allows translate this technology to other labs how wish to use organs-on-a-chip technology in their lab. This work was published in APL bioengineering (Rauti, Rossana, et al. "Transforming a well into a chip: A modular 3D-printed microfluidic chip." APL bioengineering 5.2 (2021): 026103).

Covid: During the beginning of the SweetBrain project, the world pandemic started, and we joined the world effort to get more knowledge on the pandemic. To do so, we identified which of the 29 proteins which create the SARS-Cov-2 virus, has the most significant on the vasculature. We identified that 5 proteins reduce the ability of the vasculature to protect the tissues. Furthermore, we developed a computational model to predict how each one of the SARS-Cov-2 can affect the different tissues in the body. This work was published in Elife (Rauti, Rossana, et al. "Effect of SARS-CoV-2 proteins on vascular permeability." Elife 10 (2021): e69314.).
This was extremely novel, as when we published our work, there were about 100,000 papers which are Covid-related, but less then 10 on the effect of Covid on the vasculature.
This had a major impact and received a lot news coverage including national and international media (news and TV).
In addition to the work that was published, we have new unpublished data that provides insights into the effect of glucose on the endothelium, astrocytes, and neurons, which was identified by using a human-relevant advanced in vitro platform.

Dissemination and enriching the field:
The dissemination was both in scientific journals and in other means.
Scientific journal: we published three review papers that give an overview of the field. These reviews were published in Annual Reviews, APL bioengineering and Cells and Tissue research: Hajal, Cynthia, et al. "Biology and Models of the Blood–brain Barrier." Annual review of biomedical engineering 23 (2021): 359-384.; Maoz, Ben M. "Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system." APL bioengineering 5.3 (2021): 030902; Maoz, Ben M., et al. "Technology-based approaches toward a better understanding of neuro-coagulation in brain homeostasis." Cell and tissue research (2021): 1-6.
Other means: I participated in more than 50 scientific conferences, and our work was promoted in the media (including TV, radio and newspapers).
The impact of the work that we did (and published) until now was more impactful than we could expected.
Our work on Covid was one of the first papers that identified the main vascular proteins that are effected by the virus. In addition to the fact that it had a significant impact in the media, it has more than 40 citations win less then 2 years. This work provide a significant input on the disease and provides a computational model and data that was not existing until now. and scientifically.
The platforms that we developed, is the first of a kind platform that enables labs to transform their standard lab tools to Organs-on-a-Chip, and to have in situ sensors to monitor the cellular functionality.
Currently, we develop a one of a kind human model and the neurovascular unit, and we will provide, significant insights on the effect of sugar on the brain functionality, which can lead to neurodegenerative disease.
The data and insights that will be provided in this work are unprecedented, and will have a significant effect on our understanding on the effect of glucose on the brain.
The covid paper
Smart OoC paper