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PhD Discussion: Anna Panteleeva and Miguel Gonzalez Martin
Friday, December 13 @ 10:00 am–11:00 am
Advancing Neurodegenerative Disease Research with Enhanced Brain-on-a-Chip Technology and Integrated Biosensor Systems
Anna Panteleeva
– Nanobioengineering
Neurodegenerative disorders (NDDs), such as Alzheimer’s disease, remain a critical global health challenge. A key obstacle in drug development is the blood-brain barrier (BBB), which plays a crucial role in regulating the exchange of substances between the bloodstream and the brain. While the BBB protects the brain, its dysfunction contributes to NDD progression, and it hinders drug delivery, leaving most therapeutic candidates unsuccessful in clinical trials.
Traditional animal models have provided valuable insights into NDDs, but they fall short in fully replicating the complexity of human neural responses. Brain-on-a-chip (BoC) technology has emerged as a promising tool, offering controlled environments to study neuronal networks. Integrating a BBB component into BoC systems significantly enhances their physiological relevance, enabling the study of complex BBB properties.
Our research advances BoC technology by combining a microfluidic device, multi-electrode array (MEA) technology and biosensors to create a comprehensive BBB model. By co-culturing endothelial cells, pericytes, astrocytes, and neurons, we replicate key BBB elements and neural interactions. This setup allows real-time monitoring of BBB permeability and neural activity via MEA electrodes, and neuronal degradation using biosensors. Preliminary results demonstrate promising outcomes, though further optimization is required.
This innovative approach improves the physiological relevance of BoC systems and accelerates drug development and personalized therapies for NDDs, providing a pathway toward more effective treatments.
Designing synthetic mechanosensitive molecules for the mechanical control of cellular transcription Miguel Gonzalez Martin – Cellular and Molecular Mechanobiology
Cells sense mechanical signals in the process of mechanotransduction, activating pathways that govern cell behavior. However, it remains a challenge to engineer mechanotransduction pathways in a controllable and predictable manner. Here we aim to engineer a synthetic mechanosensitive transcription factor (msTTA). To this end, we exploit the force induced changes in nuclear transport, linking nuclear mechanical perturbations to gene expression. To do so, we are mechanically tuning the passive and facilitated transport properties of the synthetic msTTA. Through this we aim to recapitulate the localization behavior of endogenous mechanosensitive proteins such as YAP or Twist, but with a synthetic factor that activates genes of choice in a controlled way. Optimizing our reporter cells, we have set up a novel screening platform with substrates of different rigidity, from which we expect to identify highly mechanosensitive TF candidates that function in a tunable manner, as well as to elucidate which features make a transcription factor mechanosensitive. Overall, we expect to unlock precise transcriptional control through mechanical forces, and a state-of-the-art directed evolution platform for msTTAs. With the simplicity of this engineered regulatory module, we expect to describe the minimal elements of mechano-regulation of gene expression, as well as enabling the use of mechanotransduction in gene circuits control. This will open the field to use mechanotransduction approaches for complex synthetic biology applications.
