Neuroenergetics: Importance of transport for the regulation of energy substrate fluxes in brain cells

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Description

Background: Brain cells were shown to rely on two energy subtrates to sustain their activity: glucose and lactate. Each of these substrates are taken up by brain cells via specific transporters and metabolized in classical biochemical pathways. The critical question remains: Between metabolism and transport, what is the limiting step for the utilization of each energy substrate under resting vs. activated condition?

Goal: The goal of the project is to determine whether transport of the main energy substrates for the brain, glucose and lactate, can become rate-limiting following an increase in cerebral activity.

Mathematical tools: The student will learn to use a mathematical software (Matlab) in order to conduct simulations from a given set of parameters and equations derived from Michaelis-Menten kinetics.

Biological or Medical aspects: The “biology supervisor” will provide background of the main aspects related to brain energy metabolism and Michaelis-Menten kinetics.

Supervisors: Luc Pellerin & Aitana Morton de Lachapelle

Students: Elita Idrizi, Céline Pattaroni & Jennifer Tscherrig

Reference:
  1. Barros LF, Porras OH, and Bittner CX. Why glucose transport in the brain matters for PET. Trends Neurosci 2005 Mar; 28(3) 117-9. doi:10.1016/j.tins.2005.01.002 pmid:15749163. PubMed HubMed [barros]

Outline

1st meeting: Fr. 27/2/09 (Luc Pellerin & Aitana Morton de Lachapelle)

  • Biological introduction + literature to read. Discussion of the goals of the project.

Media:Neuro_notes_articles.jpg


2nd meeting: Fr. 6/3/09 (Luc Pellerin & Aitana Morton de Lachapelle)

  • Introduction to derivatives, ordinary differential equations and analytical vs numerical resolution.
  • Glucose metabolism: irreversible Michaelis-Menten kinetics.
  • Graphical representation of the metabolic flux as a function of neuronal glucose, in Matlab.

Media:Neuro_Intro0.jpg Media:Neuro_intro1.jpg Media:Neuro_Intro2.jpg Media:Neuro_Intro3.jpg


3rd meeting: Fr. 13/3/09 (Aitana Morton de Lachapelle)

  • Glucose transport: reversible Michaelis-Menten kinetics.
  • Graphical representation of the net transport- and metabolic fluxes as a function of neuronal glucose, in Matlab.
  • Discussion on whether transport and/or metabolism are rate-limiting for glucose consumption by the neurons.

Media:Neuro_gluc_transp1.JPG Media:Neuro_gluc_transp2.jpg


4th meeting: Fr. 20/3/09 (Aitana Morton de Lachapelle)

  • Exercises on Matlab to solve ordinary differential equations numerically.
  • Outline of the mid-term presentation.

5th meeting: Fr. 27/3/09 (Luc Pellerin & Aitana Morton de Lachapelle)

  • Discussion of the paper by Barros et al. [1].
  • Small visit of the Physiology Institute to have an overview of the experimental techniques used (group of Luc Pellerin)
  • Preparation of the mid-term presentation.

Media:Neuro_Barros0.pdf Media:Neuro_Barros1.pdf


6th meeting - Midterm presentation: Fr. 3/4/09 Media:Neuroenergetics_midterm_presentation.ppt


7th meeting - Thur. 23/4/09 (Luc Pellerin & Aitana Morton de Lachapelle)

  • Modeling of pyruvate transformation into acetyl-coA by PDHc.

8th meeting - Thur. 30/4/09 (Aitana Morton de Lachapelle)

  • Modeling of lactate transport and metabolism, considering different cases and parameters.

9th & 10th meeting - Thur. 7/5/09 (Luc Pellerin & Aitana Morton de Lachapelle)

  • Discussion to set up the lactate model we will consider and simulate.
  • Simulations and rate-limiting factors.

Media:Notes_lactate_1.jpg Media:Notes_lactate_2.jpg Media:Equations_différentielles_lactate.jpg


11th meeting - Final presentation - Fri. 29/5/09 Media:Neuroenergetics_final_presentation.ppt


(Project in Course: "Solving Biological Problems that require Math")