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  Exploring lipids in cell biology: rebalancing lipid metabolism to dissect organelle function in lysosomal storage disorders


   London Interdisciplinary Biosciences Consortium (LIDo)

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  Prof Ulrike Eggert, Prof S Garcia-Manyes  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply

Lipids are essential but understudied biomolecules. They are key components of many cellular compartments including the plasma membrane, endoplasmic reticulum (ER), and lysosomes. Functioning lipid metabolism is therefore an essential requirement for most biological processes. Cells synthesise many thousand different lipids and carefully regulate their amounts and localisations through mechanisms that are not well understood. Mutations in lipid modifying enzymes can lead to metabolic diseases such as the lysosomal storage disorders (LSDs), including Gaucher where patients carry mutations in the lipid processing enzyme GBA, which also presents a major genetic risk factor for Parkinson’s disease. Mutant GBA changes lipid composition. We do not fully understand the biological mechanisms underlying healthy lipid metabolism, nor how mutations in proteins like GBA cause diseases.

To better understand the regulation of lipid biosynthesis and its functional consequences, we will use cells lacking GBA as a model system. We have shown that perturbation of lipid metabolism can overcome GBA-induced defects and have identified multiple lipid metabolic players that resulted in the phenotypic rescue of GBA depletion. The goal of this iCASE project is to investigate how and why changes in lipid metabolism rescues the disease phenotype. This is a conceptually new approach that will allow us to better understand at a mechanistic level how lipid metabolism interfaces with other aspects of cell biology. The discoveries made in this project will impact therapeutic approaches to LSDs and other disease as it will uncover new potential therapeutic targets in lipid metabolism.

This is a highly interdisciplinary project that will train the student in cutting edge and transferrable skills, primarily in cell biology and in lipid biology – an exciting area of science that is rapidly expanding.

In Year 1, the student will be trained cell culture and how to manipulate lipid metabolism. They will optimize imaging conditions and familiarise themselves with lipid mass spectrometry.

In Years 2 and 3, the student will analyse the lipidomes of cells where GBA and lipid metabolism have been perturbed. We will use mass spectrometry to conduct comparative lipidomics on cell extracts and fractionated organelles like lysosomes and the ER and will use a rage of techniques including atomic force microscopy and imaging for the biophysical characterisation of newly identified lipids (with Sergi Garcia-Manyes). In parallel, the student will use functional assays to analyse the effect of lipid changes on e.g. lysosomes, the ER and endosomal transport using, for example, imaging assays established in the Eggert lab. In Y3, especially during their placement at Sanofi/Genzyme, the student will broaden their results from cultured cells to more physiological experimental models.

In Year 4 the student will finish data analysis and will write their thesis and papers stemming from this work.

This project will be in collaboration with the multinational pharmaceutical company Sanofi. The student will be mentored throughout the project by Dr. Can Kayatekin, a Principal Scientist in the Rare and Neurological Diseases Therapeutic Area located in Cambridge, MA, USA. This group is world- and industry-leading in their efforts to understand lysosomal storage disorders and to develop assays to investigate the many aspects of these diseases. During their three month placement in Dr. Kayatekin’s group, the student will get both a thorough understanding of the fundamental biology involved in GBA-related processes as well as gain immersion learning on how research is conducted in a large pharma company. This knowledge will be invaluable to their scientific development, giving the student a first hand view of how science is performed in an industry setting and building a network outside of academia.


Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,609.