New grants to Gether, Vosch, Løland and Kampranis

The Danish Ministry of Higher Education and Science sent out a press release announcing the receivers of their 2017 DFF-Research project grants. Among the receivers are 4 synbio center associated scientists; Professor Ulrik Gether and Ass. Professors Tom Vosch, Claus Løland and Sotirios Kampranis.

Ulrik Gether

Projec title: The dopamine ‘transceptor’: new insights into the multifaceted cellular action of amphetamines
Abstract: Amphetamines are being abused increasingly, in addition to the fact that drugs are often used to treat ADHD. However, we have surprisingly poor insight into the effect of amphetamines on cellular levels. The psychostimulatory effect of amphetamines is linked to their uptake in dopaminergic neurons via dopamine transport (DAT). Through unclear mechanisms it triggers "reverse transport" where dopamine is released to synapse. In the project, we will seek to understand how DAT can act as a "transceptor" through which amphetamine can activate intracellular signaling cascades, and how these, in addition to causing "reverse transport", can cause adaptive changes in neuronal functions. Using newly developed genetic tools, we will clarify the effect of amphetamine on Ca2⁺ and cAMP-mediated signaling in dopaminergic neurons and how it can trigger immediate-gene activation. Next, we will seek to understand the effect of amphetamine on DAT using mass spectrometric methods to map amphetamine-induced changes in the complex of DAT-binding proteins. Finally, we will seek to understand the importance of G protein coupled receptor signaling cascades for the effect of amphetamines and apply special "designer receptors". Overall, we expect the project to lead to a new understanding of amphetamines' cellular effects that can both change our perception of transport as drug target and lead to new treatment strategies for dopaminergic diseases.
Amount: 2.6 M DKK

Tom André Jos Vosch

Project title: Single Molecule Absorption Spectroscopy
Abstract: Clusters of a few silver atoms have been found to have exciting optical properties including fluorescence. However, the properties of these photophysical clusters are not well understood, especially the relationship between structure and properties is not understood. The project aims at investigating the cluster's photophysics on the single molecule level. We will use broadband excitation spectroscopy to study individual clusters' spectral properties. This will allow us to design more photostable fluorophores that are good emitters. We expect these to find use in vitro and in vivo applications.
Amount: 2.5 M DKK

Claus Juul Løland

Project title: Elucidating the role of potassium in the molecular function of neurotransmitter:sodium symporters
Abstract: Neurotransmitter:Sodium Symporters (NSSs) ensure cellular function by utilizing the Na⁺ gradient for the uphill transport of solutes. We have recently found that the structural model protein for NSSs, the bacterial NSS LeuT, do not only use Na⁺ for transport, but also intracellular K⁺, a feature only previously observed for the serotonin transporter (SERT). This opens for the possibility that K⁺ binding is a common, yet un-investigated mechanism in NSS proteins. The purpose of the current project is to characterize the K⁺ binding site in LeuT and SERT in terms of its location and molecular function. We will, on purified protein, determine the K⁺ binding site by site-directed mutagenesis and transition metal ion FRET. The role of K⁺ binding on the transport function is investigated with reconstituted systems where the purified protein is inserted into a lipid bilayer. We will also perform crystallization trials on LeuT together with Rb⁺ substituting for K⁺ for direct determination of its location in the protein. Finally, we will assess whether K⁺ binding is a more common feature also present in other NSSs such as the dopamine transporter.
Amount: 2.6 M DKK

Sotirios Kampranis with Søren Bak

Project title: A comprehensive approach to the production of the bioactive cucurbitacin triterpenoids
Abstract: Cucurbitacins are the bitter triterpenoid compounds found in wild squash, watermelon, and cucumber. They have an immense pharmacological potential as anti-cancer, anti-diabetic and immunomodulatory agents, but their use is hampered by their low levels. We will overcome this limitation by developing two parallel complementary approaches to establish the confined and sustainable biotechnological production of cucurbitacins. The proposed research plan combines two production platforms, yeast and hairy-roots, in an integrated manner which combines advantages of both systems to characterize cucurbitacin biosynthesis and produce specific compounds. The yeast platform will enable the combinatorial biosynthesis of cucurbitacins and cucurbitacin-like molecules, while the hairy root platform will mainly provide scale up of cucurbitacins of a defined and known structural composition.
Amount: 5.8 MDKK