Author Archives: niamhconno

Final Project: Eric Yixin Yang – Mathematical Model of Autophagy Activation Pathway

Autophagy is a highly orchestrated degradative process that sequesters and degrades damaged or excess organelles in response to internal and external stress including starvation, oxygen limitation, microbial invasion and hormonal stimulation. The understanding of biochemical pathway of autophagy is important in determining the fate of cells that respond to stress including the challenge of chemotherapeutic agents. This project attempts to build a mathematical model for the activation of autophagy by nutrient deprivation (low concentration of amino acids) with feedback loop when the amino acids generated by protein lysosomal degradation increases the amino acid pool. To achieve this goal, I use MATLAB and XPP learned from the CSHL CCB summer course to build this model and do analysis. The model successfully simulates the change of amino acid level as a response to different nutrient status by autophagy. The system displays oscillation of amino acids level in both nutrient starvation and nutrient enriched status, but does not shows oscillation if starting from the steady state. Total amino acids eventually reach the same level regardless of the initial nutrient status. The bifurcation analysis confirms the simulation result.

Final Project: Niamh Connolly – Parameter optimisation for a model of AMPK-mediated survival signaling

Glutamate excitotoxicity is a pathological process implicated in stroke, traumatic brain injury and numerous neurodegenerative diseases. In culture, neurons exposed to the same excitotoxic stimulus can either survive the insult or undergo rapid necrotic or delayed apoptotic cell death. In our lab we are investigating the regulation of this switch-like behaviour. Using fluorescence data obtained in single neurons, we observed that ATP and AMPK rapidly recovered to homeostasis following transient excitotoxic perturbation. In contrast, the recovery of glucose was significantly slower. Interestingly, the extent of this delay correlated with the duration of subsequent survival.

To investigate this behavior from a computational perspective, I previously developed a MATLAB ODE-based model based on prior knowledge of signalling pathways. The model correctly resembled ATP and AMPK kinetics, but failed to resemble the delayed glucose recovery.

In this project, I implemented my model in both Virtual Cell and COPASI, and used the inbuilt parameter estimation functions to fit the glucose response. I confirmed that the model in its current state cannot completely explain the observed glucose kinetics. I next incorporated additional model reactions in an attempt to explain the discrepancy in glucose behaviour. However, extensive parameter estimation for this updated model failed to simultaneously fit the glucose response curve for both the steady-state and perturbation situations. Further analysis is necessary to identify specific reactions that can delay the glucose recovery without simultaneously affecting ATP.

Project Idea: Mathematical model of autophagy activation pathway – Eric Yang [Jalil]

Autophagy is a highly orchestrated degradative process that sequesters and degrades damaged or excess organelles in response to internal and external stress including starvation, oxygen limitation, microbial invasion and hormonal stimulation. The understanding of biochemical pathway of autophagy is important in determining the fate of cells that respond to stress including the challenge of chemotherapeutic agents. This project will build a mathematical model for the activation of autophagy by nutrient deprivation (low concentration of amino acids) with feedback loop when the amino acids generated by protein degradation increases the amino acid pool. I am especially interested in how the amino acid level affects the activation of autophagy and how the feedback parameter (due to autophagic degradation of protein) influences the concentration of total amino acid.

Project Idea: Parameter optimisation for a model of AMPK-mediated survival signalling – Niamh Connolly [Albert]

I would like to investigate a model of AMPK-mediated survival signalling during transient neuronal excitotoxicity (pathway hypothesised by Weisova et al (2009), J. Neurosci. http://www.jneurosci.org/content/29/9/2997.long). I have previously implemented a version of this model in MATLAB, with manual parameter optimisation. I managed to fit the model to experimental data for two of the state variables (ATP and AMPK), but have not been able to fit a third state variable (glucose).

For this project, I will implement the model in VCell, and perform parameter optimisation using the inbuilt functions. I will also perform parameter optimisation in COPASI (and maybe MATLAB SimBio). I would like to be confident that the model in its current state is unable to adequately represent the entire dataset, and investigate what additional reactions may be required.

* This project proposal was written using British English spelling…….!

Niamh Connolly, Royal College of Surgeons in Ireland

Niamh Connolly