In addition to the many projects developed by the members of the lab based on their interests, collaborations and opportunities, we are funded to participate to specific projects. This page presents the most prominent ones. Links in each section leads to more details.
SynSys stands for ‘Synaptic Systems’. A project funded by the European Commission, SynSys aims at molecular analysis of synapse function and dynamic modeling. The perspective is to generate a blueprint for the discovery of novel pathways and targets that enable rational strategies to design therapies for human brain disease. More information is available here and on the SynSys website.
Information about the November 2012 SynSys Modelling meeting.
AgedBrainSYSBIO is a project funded by the European Commission to unravel the biochemical pathways underlying the synaptic disorders associated with neurodegenerative diseases and in particular Alzheimer disease. The main goals addressed by the consortium will be:
- Identify and reconstruct physical and functional interactomes involved in late onset Alzheimer disease (LOAD) using genome wide association studies (GWAS) and proteomics approaches.
- Identify and reconstruct the corresponding biochemical pathways.
- Manipulate those pathways in animal models and human induced pluripotent stem (IPS) cells.
- Design drugs and intrabodies to target the main pathways involved in the disease etiology.
More information can be found on the AgedBrainSYSBIO website.
A systems approach to understanding lipid, Ca2+ and MAPK signalling networks.
Sensing and interpretation of external stimulus by the cell often involves the recruitment of several cross-regulating signalling pathways. For many years we have studied the biochemical determinant of neuroadaptation by the medium-sized spiny neuron of the striatum. In this model, synaptic plasticity and dendritic remodeling, involve several intracellular kinase-dependent signalling pathways acting with different timescales. For instance, CaMKII, PI3K and PKC trigger short-term plasticity in seconds through protein modifications and translocation. PKA, ERK (MAPK) and CaMKIV persistently modulate gene regulatory networks and change gene expression. TrkB, a tyrosine kinase receptor for neurotrophins and PI3K/PKB are also involved in long-term effects on for instance dendritic remodelling and neuronal survival. All these kinase pathways are linked through the activation/inhibition of phosphatases, ultimately forming a network of kinases, phosphatases and substrate phosphoproteins with variable dynamics. However, at present the knowledge of these phosphorylation-dependent signalling pathways remains fragmented and largely descriptive.
Our activity within the signalling Institute Strategic Programme follows two lines:
- we will continue to study the role of Ca2+ signals in synaptic plasticity, developing highly realistic models. Those models will help in understanding the respective roles of the proteins constituting the Ca2+-sensitive, long-term potentiation cycle - glutamate ionotropic receptors, calmodulin, neurogranin, calcineurin and CaMKII – in decoding amplitude, frequency and duration of Ca2+ signals. A better grasp Ca2+ homeostasis and dynamics is now acknowledged to be a key to understanding synaptic ageing.
- We will use synaptic signalling as a model system to understand the mechanisms and consequences of integrating multiple signalling pathways. The initial focus will be, in addition to Ca2+, on MAPK cascades and phosphoinositide signalling.
How do cells shape and interpret PIP3 signals?
Class I PI3K signaling is one of the most important signalling networks in mammalian cells and is under intense investigation by the pharmaceutical sector. However, many of the underlying principles by which it operates are still unknown, thereby limiting our understanding of many aspects of biology, such as cell migration and growth, and hindering drug development. In collaboration with the group of Len Stephens and Phil Hawkins, we tackle this problem by applying a combination of novel lipidomics, modern cell biology and modelling methods to understand the key factors that shape PIP3 signalling in response to hormones and oncogenic mutation in a non-transformed, human, breast epithelial cell line. More information can be found on the BBSRC website.
Differentiation and Re-programming of Stem Cells
Research on differentiation and re-programming of stem cells is the initial step towards on development of re-generative medicine. Success of artificially constructed organs on model organisms are promising, and progressing towards clinical trials on human patients. The data collected from such studies can be used to build and train a whole organ model, which can be used to simulate plausible scenarios to improve the artificial organs being designed.
Our aim is to build dynamic mathematical models of stem cells to describe their differentiation and re-programming. Our strategy is building modular models at all levels (i.e., signalling, epigenetics, transcription, translation, cell division) and merging these modules with the ultimate aim of building a whole-cell of model of stem cells.
A system-wide model (may it be focusing on a whole-cell, whole-organ or whole-organism) will involve modular mathematical modelling, as representing all cellular processes in a single model will not be practical for a number of reasons (e.g. need for specific mathematical formalisms and specific simulator software for each process, inefficient use of computing power, difficulty of updating a big model when more information becomes available). Hence, our secondary aim is to develop an algorithm for efficient parallel simulation and synchronisation of modular mathematical models.
Click here to read more about this project.