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4 Year MRC PhD Programme: Chagas disease: Understanding parasite tissue tropism and the tissue drug distribution requirements for successful drug development using Mass Spectrometry Imaging (MSI


About This PhD Project

Project Description

Treatment of T. cruzi, the causative agent of Chagas disease has proven extremely challenging, in part due to its complex life cycle in mammalian hosts. There is growing evidence that the parasite resides in difficult to access, immune privileged sites such as ovaries, testis and brain in both acute and chronic disease. Furthermore, the parasites are consistently detected in lymph nodes in chronic disease adding further challenge to developing the right properties in a chemotype to deliver the distributional requirements necessary for sterile cure. Exploring and understanding whether lymph acts a reservoir or just a transient pool for parasites will be critical to this end. Consequently, the ability to better detect both parasites and drug in difficult to access tissue and different tissue regions following treatment in mouse models of infection would add significant value in our understanding of this disease and the drug distributional requirements necessary for treating this disease.

Advances in Mass Spectrometry Imaging (MSI) technology now allows for sub-cellular resolution with SIMS, and MALDI or DESI, with a suitable high resolution MS, are often utilised for drug concentration measurements in tissue. Furthermore, although the spatial resolution in MALDI is not sufficient for detection of the parasite it may be possible to use a lipid signature to determine whether parasite is present and combine this with ability to determine drug concentration.

This project will utilise a number of MS approaches on a range of tool compounds to help better understand parasite and drug distribution and consequently the properties needed for a small molecule treatment for Chagas disease.

The student will work in a drug discovery setting, learning industry standard assays for assessing drug and parasite tissue distribution and building expertise in use and application of state of the art mass spectrometry imaging techniques including MALDI, DESI and nano-SIMS to help answer some of the key challenges facing development of a new drug treatment for a neglected tropical disease.



References

Goodwin, R.J.A. et. al., Anal. Chem.,2011,83(24),9694
Norris, J.L. and Caprioli, R.M., Chem. Rev., 2013,113(4),2309

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