AIAS-COFUND (Marie Curie) Fellowships

Aarhus Institute of Advanced Studies (AIAS) AIAS-COFUND Fellowships are available for talented researchers. The scheme is co-funded by Aarhus University's Research Foundation and the European Union’s 7th Framework Programme under grant agreement no 609033 and provides research opportunities for the most talented researchers from around the world.

Magnus Kjærgaard

AIAS Cofund Junior Fellow

Project: Can a cooked noodle store information? The mechanisms of disordered proteins in synaptic plasticity

Learning and memory depends on the ability to modulate the connections between neurons in the brain in a process called synaptic plasticity. An important mechanism in synaptic plasticity involves the proteins sensing chemical signals at synapses, neurotransmitter receptors. The NMDA receptor is a neurotransmitter receptor with a key role in learning, which depends on its large intracellular domains. The intracellular domains are intrinsically disordered, are the target of many kinases and bind to many other proteins. Despite its importance, we know little about how the intracellular domains regulate the receptor mechanistically, and little about how intrinsically disordered proteins can exert long-range regulatory effects in general. This is largely due to the almost complete lack of structural information on the intra-cellular domains.

In this project, I will study the intracellular domains of the NMDA receptor using a combination of NMR spectroscopy and single molecule FRET. Structural experiments will be complemented by functional measurements using electrophysiology in Xenopus oocytes. The goal is to identify the mechanism by which the intra-cellular domains affect synaptic plasticity on short time-scales, and how this effect is modulated by phosphorylations and ligand interactions. This will provide another piece of the enigma of how the many wonderful functions of the brain emerge from chemical and physical processes.


 

Project: How do we sense touch, sound, balance and force?

Project description

Perception of force is a key component in our sense of touch, hearing, balance and pain as well as in regulation of blood and osmotic pressures. Fundamental to these concepts is that at some point force (newtons) is translated into electrical conductance (siemens) through the action of membrane embedded mechanosensitive channels that open or closes in response to changing forces in the lipid bilayer. Conceptually this is perfectly conceivable, but it is astonishingly little we know about the mechanism of how bilayer responses are converted into changes in channel activity. So unlike the well-described nature of taste and odorant receptors and the photoreceptors in the eye, we have not yet a clear idea of how our mechanosensitive receptors work.

When studying the relationship between lipid membrane and embedded proteins the major challenge is that, in contrast to stimulation with e.g. ligands or voltage, we don’t really know the exact nature of our stimulation; we can poke or pull a cell, but we cannot quantify what the channel actually feels at a molecular level.

To increase our understanding of functional interactions between lipids and protein, we will use a minimalist approach by developing novel assays that utilize a set of molecular tools to manipulate specific forces in the membrane, while at the same time taking advantage of the detailed information available from singe channel recordings. 


Bjørn Panyella Pedersen

AIAS Cofund Junior Fellow

Project: Mechanisms behind cholesterol and sugar uptake 

The project supported by my AIAS fellowship addresses fundamental scientific questions pertaining to an essential membrane transport system in humans; namely facilitated sugar transport, where new insights will have immediate scientific impact.

Facilitated sugar transport is the process by which sugar-molecules are taken up from circulation into the individual cells of the body as an ubiquitous energy and carbon-source. Furthermore sugar uptake contributes to the generation of reducing power in the cell.

Facilitated sugar transport in humans is made possible by sugar transporters called GLUTs and SWEETs located in the cellular membrane, and every cell possesses these sugar transport systems. For both GLUTs and SWEETs, structural information is sorely lacking to address important mechanistic questions to help elucidate the molecular mechanism by which they can move sugars across the cellular membrane in a efficient manner. I will address these systems using a complementary set of methods founded in macromolecular crystallography to elucidate 3-dimensional structure.

Promising preliminary results have established the feasibility of this approach. This will be followed up by characterization of the molecular mechanism in vitro and in silico, probing e.g. partner interactions, inhibitors and mutations. Parts of the characterization will be conducted in association with a well-established network of national and international collaborators.

The proposed work will help to uncover general principles of facilitated diffusion systems. Furthermore an improved understanding of sugar homeostasis in humans has tremendous potential for improving general public health, and the proposed work will stimulate pharmacological efforts to identify and develop compounds of therapeutic value for e.g. obesity, diabetes and cancer.