Cell membrane nanomechanics: implications of glycosphyngolipids linked to Lysosomal Storage Disorders.

Group:  Nanoprobes and nanoswitches and Targeted therapeutics and nanodevices
Group leader: Marina I. Giannotti (migiannotti@ibecbarcelona.eu) and Silvia Muro (smuro@ibecbarcelona.eu)

Research project

Biological membranes are active players in cell and organelle architecture and function, and the mechanical role of the membrane in force triggered/sensing mechanisms is gaining increased attention, particularly regarding how this depends on its specific and local lipid composition, which is under a tight homeostatic control.

Numerous links have been established between lipid imbalances and human pathologies, e.g. for lipid-related metabolic conditions like the lysosomal storage disorders (LSDs). LSDs are rare inherited chronic diseases, characterized by the deficiency of specific lysosomal enzymes. Some of these enzymes are involved in lipid catabolism, e.g. Fabry (FD) and Gaucher diseases (GD), in which the accumulation of undegraded glycosphingolipids (GSLs) alters the metabolic flux and cellular processes mediated by membranous structures. For instance, trafficking of endocytic vesicles is affected due to the abnormal lipid composition of membranes. This worsens the disease and impairs the success of approaches which depend on endocytic trafficking to deliver therapeutics into diseased cells.

Our goal is to understand at the nanoscale and molecular level the implications of the membrane structural and nanomechanical reorganization in response to the abnormal GSL accumulation in LSDs, and to correlate this with the cell mechanics and affected membrane-related pathways in vitro in FD and GD. We will use nanotechnology tools like atomic force microscopy-force spectroscopy, in vitro membrane models, cell biology techniques using patient cells, and the design of therapeutic interventions. We anticipate obtaining an outline of the correlation points between the altered membrane biophysics and endocytic pathways in LSD, to help us design less toxic and more effective therapeutic tools, e.g. combining the delivery of enzyme replacement therapies with drug-induced regulation of membrane biophysics for improved treatments.

Job position

We seek for a candidate with an interdisciplinary profile (background in biophysics, chemistry, nanoscience, physics, biology, pharmacy, or related).  The candidate will work on the design of membrane models for LSDs, the biophysical characterization of the membranes including the nanomechanical evaluation and membrane remodeling upon enzymatic hydrolysis using atomic force microscopy and spectroscopy. The candidate will also work with in vitro FD and GD cell mechanics, cellular trafficking/endocytosis experiments, and the design and testing of potential therapeutic solutions. He/she will receive the necessary training for the mentioned techniques and will develop the experimental work in the facilities of IBEC, at the “Nanoprobes & Nanoswitches” and the “Targeted therapeutics and nanodevices” groups. In addition, the PhD will benefit of the training environment of IBEC, institution that is strongly compromised on preparing researchers from the undergraduate up to postdoctoral level.