Membrane biophysics to understand rare Lysosomal Storage Disorder

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

Numerous links are established between lipid imbalances and human pathologies, as in metabolic conditions like the lysosomal storage disorders (LSDs). LSDs are rare inherited chronic diseases characterized by the deficiency of specific lysosomal enzymes. For example, in Fabry (FD) and Gaucher diseases (GD), the accumulation of undegraded glycosphingolipids (GSLs) affects not only the metabolic flux but also causes intracellular “traffic jams”. We are interested in the active participation of lipid bilayers in the overall membrane processes and cell mechanics. Cells regulate the membrane composition such that common biophysical membrane parameters are under homeostatic control; however, this is affected in LSDs that associate with lipid metabolism. Additionally, normal endocytic trafficking can be altered in LSDs, which may have a direct impact in drug delivery therapeutic approaches. Can we understand the pathology of these rare diseases by looking at the physics of their membranes? Will this assist future development of more effective treatments?

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 further establish the correlation with the cell mechanics and affected membrane-related pathways in vitro in FD and GD. We focus on the application of nanotechnology biophysical tools like atomic force microscopy-force spectroscopy and the design of membrane models and in vitro observations. We anticipate obtaining an outline of the correlation points between the membrane biophysics and the endocytic pathways on LSD cells. Understanding the mechanism behind altered membrane processes in LSDs will generate significant insight for future design of less toxic and more effective drug delivery systems, combining strategies of enzyme delivery 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 and cell traffic/endocytosis experiments. 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 & Nanoswithces” 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.