We are interested in the factors that drive cell death susceptibility in Alzheimer’s disease and Brain Cancer, in order to exploit mechanisms for neuronal protection. We know that a number of pathways related to autophagic flux, protein degradation, axonal transport, mitochondrial fusion & respiration as well as tubulin stability are implicated. Central is ATP availability, especially in the compartmentalized regions where the ATP demand is highest. Pathways for neuronal migration and plasticity rely on a highly functional actin, tubulin and mitochondrial network interplay, which allow us to better understand the susceptibility for undergoing a network collapse and metabolic failure, changing the cell’s matrices for apoptosis or necrosis onset. Lastly, we aim to exploit the relationship between ATP availability and apoptosis onset in context of astrocytomas, in order to maximize cell death through sensitization. Central to all of the above is the accurate and robust quantification of autophagic flux, the rate of protein degradation through autophagy, in order to control it with highest degree of precision.
Therefore, the focus of our current research projects concern both 1) the role of autophagy in disease pathogenesis and 2) the regulation and control of autophagic flux.
1. THE ROLE OF AUTOPHAGY IN DISEASE PATHOGENESIS
Given the involvement of autophagy dysfunction in both neurodegeneration and tumourigenesis, we are interested in the following ares:
The role of autophagic flux in the context of neurotoxicity.
How autophagic activity alters substrate metabolism and mitochondrial function.
How to beter utilise intervention strategies such as autopaghy modulators, nutrient starvation or ketone bodies to protect neurons from cell death or to induce it in gliomas.
2. REGULATION AND CONTROL OF AUTOPHAGIC FLUX
Systems biology is uniquely equipped to address questions central to cellular physiology, especially in terms of complex network regulatory mechanisms. Our group includes therefore a systems biology approach, where suitable, to the autophagy regulatory network. In particular, we currently focus here on:
Flux assessment and control analysis of protein degradation through autophagy.
Constructing robust mathematical models and high throughput measurement tools of autopaghic flux.
The relationship between autophagic flux and cell death prediction.