We are interested in understanding the roles of spatial organization in biological processes such as membrane receptor activation and signal propagation within and between cells. To this end, we develop new tools that enable manipulation and analysis of the spatial organization of biological systems from nanoscale to tissue levels. We aim to contribute to a new paradigm in drug development founded on the understanding of the biophysical context of target proteins.
Membrane proteins often display non-uniform, dynamic spatial distributions. However, we know surprisingly little about how the nanoscale spatial distribution of membrane proteins and their lateral mobility affect their functions. With most drugs targeting membrane proteins, there is a need to understand the modes of biophysical regulation of membrane proteins and to overcome methodological roadblocks to analysing and controlling the organization of membrane proteins at the nanometer to 100-nanometer lengthscale. We use DNA nanotechnology as a tool to achieve this due to its tailorability and precision.
We developed NanoDeep-a non-microscopy based super resolution method for unbiased analysis of protein nanoenvironments at the nanoscale that translates spatial organization information into a DNA sequencing readout. NanoDeep has the potential to provide a breakthrough in the analysis of the spatial distributions of hundreds of proteins simultaneously with super-resolution (Ambrosetti et al., Nature Nanotechnology, 2020).
We are addressing the hypothesis that the nanoscale spatial organization and lateral mobility of membrane receptors regulate their functions. We use DNA nanostructures as scaffolds that are modified with proteins at defined positions. Using this method, we found that the nanoscale spatial distribution of ephrin-A5 ligands regulates the levels of activation of EphA2 receptors and downstream signalling (Shaw, Lundin et al., Nature Methods, 2014; Verheyen, Fang, et al., Nucleic Acids Research, 2020).
To understand protein transport within single muscle cells and between muscle and other tissues, we use microfluidics and mathematical modeling. We found that the propagation of nuclear proteins within skeletal muscle cells could be predicted based on size, nuclear import speed, and ability to diffuse across the nuclear pore. Further, using a microfluidics model, we found that neurturin is a mediator of PGC-1α1-dependent retrograde signaling from muscle to motor neurons (Taylor-Weiner, Grigsby et al., PNAS, 2020; Mills, Taylor-Weiner et al, Molecular Metabolism, 2018).