CBC MRes Conference 2008 prize winners

Congratulations to CBC students Robert Felstead and Claire Grignolo who were awarded prizes for the best presentations at the annual CBC MRes conference.

Claire Grignolo - "Gadolinium in a box as novel MRI contrast agent"

Magnetic Resonance Imaging (MRI) is among the most used imaging techniques in clinical and experimental settings: this non-invasive diagnostic modality provides both functional and anatomical information with no use of harmful high-energy radiation (e.g.: PET, X-rays). To increase the intrinsically poor sensitivity of NMR and decrease the long nuclear relaxation times (T1 and T2), a large proportion of MRI studies are performed using contrast enhancing agents (CA) on which research has focused with the aim of shortening acquisition times and improving the diagnostic information of the images.

The only clinically approved T1 agents are monomeric chelates (e.g.: DOTA, DTPA) based on Gd3+, a lanthanide ion with 7 unpaired electrons creating a permanent magnetic field that interacts with nearby H2O protons via a dipolar mechanism to increases their relaxation rate. Relaxivity of macromolecular CA (i.e. efficiency in catalytically decreasing T1) depends mainly on the reorientational correlation rate (“tumbling”) of the molecule (1/τR): it can be enhanced by increasing the MW of the macromolecule while ensuring the Gd3+ chelates it comprises have the lowest possible degree of freedom [Aime 2005].

To achieve this, we tested a range of unique polymers (synthesised via reactions between diazide linkers and tetralkynyl DOTA) where Gd3+ chelates are incorporated “inside” the macromolecules rather than exclusively on the surface. By “trapping” the Gd3+ chelates in the polymer we expected to limit their degree of internal freedom, hence limiting the effect of local motion on the overall tumbling rate.

The relaxivity values obtained were 1.5 to 2.5 times higher than those obtained for the monomeric Gd-DOTA complex used as a starting material, indicating potential benefits of these polymeric compounds. Toxicity tests gave varying results depending on the synthetic pathway used to produce the compounds. The causes of the negative responses are being investigated. The hypothesis is that toxicity is due to an interaction between cells and unreacted azide linkers.

Robert Felstead - "Histone deacetylases: a chemical genetics approach"

Histone deacetylase inhibitors have shown great promise as anti-cancer agents as well as being implicated in neurodegenerative diseases such as Huntingdon’s. Common inhibitors such as SAHA and Trichostatin A inhibit all 11 histone deacetylases (HDACs) that contain Zn2+ in their active site. As a result there is a great deal of interest in finding isoform selective inhibitors and to examine their therapeutic potential. The novel application of chemical genetics to undercover the impact of isoform selectivity without the difficult task of actually achieving it is hereby proposed. Expression of two mutant HDACs has been undertaken as well as the synthesis of several inhibitors that should selectively inhibit the mutants over the wild-type.  If successful, the effects of selective inhibition on cell systems may then be observed and hopefully identify the effects of selective inhibition without the arduous task of finding selective inhibitors.