Biological Projects

Type 2 Diabetes and insulin signalling

The research of Gunnar Cedersund has almost from the beginning hovered over glucose homeostasis and type II diabetes. These projects have included: electric activity and insulin secretion in beta cells, metabolism in muscle, whole-body interactions between the organs, and insulin signalling in fat cells. This rather large span of projects has naturally led me to the interest in integrating the ongoing specific projects. In practice, this integration occurs through something denoted hierarchical multi-level modelling, which means that the detailed cellular models are fitted into a whole-body model. In practice these developments are starting with the Dalla Man model, which has been accepted by the FDA as a possible replacement for test animals when certifying a new drug. Into this model we then fill in intracellular details regarding the other organs. Regarding adipocytes, these details now includes a first detailed understanding of how insulin resistance occurs in type 2 diabetics (paper). These developments are done in close collaboration with the group of Peter Strålfors experimental group, who is leading the experimental side of these projects. More generally, however, we are also interacting with a number of other research groups, and in December of 2012, we arranged a first Ph.D. course on the topic, where we learned about and worked with the integration of models for all relevant organs.

Liver

The other main medical research field concerns the liver. Here we make use of the integrated research facilities at CMIV, here in Linköping, which contains experts on image analysis, radiologists, hepatologists, liver surgeons, etc - all working together to create new and improved treatments for liver patients. More specifically, we make use of MR images in combination with mathematical modelling, to be able to draw more specific diagnosis than is possible by image analysis alone. There is one Ph.D. student who is working with this project, Mikael Forsgren, and the experimental side is coordinated by Prof Peter Lundberg. In summary, we are trying to establish ourselves as the link between mechanistic and possible multi-level modelling of the liver occuring for instance within the Virtual Liver Network, and the clinically relevant modelling that can make a difference in actual healthcare. Here is a link to a talk that outlines this project.

Brain

A more recent initiative concerns mathematical modelling on neurological research. This research is done on two different levels, the cellular/electrophysiological level and the whole-brain level, but the long-term goal is to utilize multi-level modelling also here. The lower level is done in collaboration with Björn Granseth, who looks at brain cells from cortex that are involved in epilepsy. More specifically, we are looking at a behaviour known as facilitation, which means that cells are non-linearly stimulated by repeated stimulations: the response to later stimulations are much higher than the response to initial stimulations. Our mathematical models unravel different hypothesis that can and cannot explain such a behaviour. On the high, whole-brain, level we are utilizing fMRI images from patients and healthy human subjects doing various tasks. These images give a time-dependent view of the brain activity, and these activity-patterns contain information regarding how different parts in the brain are communicating with each other. This information, however, is not readily available by mere inspection, but requires advanced tools from data-analysis and mathematical modelling. This project is done by Ph.D. student Karin Lundegård, who also is supervised by Maria Engström, who is an expert on fMRI, and Fredrik Elinder, who also is an expert on cell biology and electrophysiology. Here is a link to a talk that outlines the first of these two levels.

Heart

The final medical field where we are working actively is the heart. Here we are also studying a phenomenon that has to do with the response to repeated stimulations: desensitization. This means that new stimulations that follow shortly after big prior stimulations give a smaller response. This is one of the mechanisms that has to do with heart attacks. Using mathematical modelling, we are unravelling various intracellular signalling networks that can and cannot explain this phonemonen. These networks involve players like beta-receptors and cAMP. The experiments are done by the group of Jordi Altimiras. Here is a link to a talk that describes this research.

Yeast

After from medically applied research, we are also doing some basic research, primarily on yeast, and primarily in collaboration with the group of Alejandro Colman-Lerner, in Buenos Aires. There we are studying various phenomena that vary from cell to cell, and thus allow us to understand cell-to-cell variation. The experiments are primarily done using fluorescent reports that can be seen in a microscope, and some of the systems we have looked at include the protein Ace2, the players in the pheromone response, and the fluroescent protein YFP. The modelling in this side is done e.g. by Ph.D. student Rikard Johansson.