Biophysics of Immune Cell Signalling The immune system protects our bodies from extrinsic as well as intrinsic sources of harm. Malfunction of immune cells leads to serious disorders such as cancers, infections, and autoimmune diseases. Key to the success of the immune system are the complex yet perfectly coordinated signalling mechanisms that immune cells use to distinguish friend from foe, guiding their attacks on external pathogens and malfunctioning endogenous components (e.g. cancer cells). Thus, understanding the mechanisms of immune signalling is essential for development of efficient therapeutic approaches against cancer, infection, and auto-immune diseases.
We aim to understand the physical principles underlying immune signalling.
Our Collaborators:Simon Davis (Oxford), Mike Dustin (Oxford), Petter Brodin (Karolinska), Bjorn Onfelt (Karolinska), Evren Alici (Karolinska)
Key publications: Jenkins et al, JCS, 2018; Felce&Sezgin et al, Science Sig, 2018
Development of Super-Resolution Techniques Signalling processes at the plasma membrane occur at very fast temporal and small spatial scales. Therefore, studies aimed at a thorough molecular understanding of cell signalling require advanced super-resolution techniques with nanometre and microseconds spatiotemporal resolution that can capture the molecular interactions.
We constanty develop, modify and apply advanced imaging and spectroscopy tools to reveal the nanoscale mysteries of cells.
Our Collaborators: Hjalmar Brismar (Karolinska) Key publications: Sezgin et al, Biophy Jour, 2017; Schneider et al, Nano Letters, 2018; Sezgin et al, Nature Protocols, 2019
Development of Synthetic Biology Tools Thorough investigation of cell signalling has so far been hampered by the complex structure of the cell membrane. To clarify the biophysical and physicochemical principles underlying cell signalling at the molecular level and discern the essential drivers of the processes, well-defined synthetic biology tools with controllable molecular specificity and complexity are required.
We develop bottom-up and top-down synthetic biology tools to pinpoint the physicochemical principles underlying biological processes. Our tools span from lipid-only systems, to model vesicles with specific lipids and proteins, to plasma membrane vesicles with modular reconstitution of proteins, cytoskeleton and energetic processes, to finally live primary cells.
Key publications: Sezgin et al, Nature Protocols, 2012; Cespedes et al, FEBS Journal, 2019
Cell Membrane Structure and Dynamics The cellular plasma membrane is a heterogeneous structure composed of various types of lipids and proteins, and this heterogeneity plays crucial roles in cellular signalling. The underlying physicochemical principles have been extensively studied for many years, however our understanding of cell memrbane structure is fairly limited.
By applying above mentioned technologies as well as biochemical methods and lipidomics, we aim to elucidate how the cell membrane is organised at nanoscale. We are particularly interested in lipid-lipid and lipid-protein interactions at the plasma membrane and their role in cellular physiology.
Our Collaborators: Ilya Levental (Texas), Ed Lyman (Delaware)
Key publications: Pinkwart et al, JBC, 2019; Sezgin et al, Nature Reviews, 2017
Cholesterol is trasported through the body with lipoprotein particles. High-density lipoprotein (HDL; so known as "good cholesterol") transfers cholesterol from the body cells to the liver to get rid of access cholesterol in the body. Low-density lipoprotein (LDL; so-called "bad cholesterol"), on the other hand, delivers cholesterol to the body. This balance of lipoproteins is key for health and imbalance leads to cardiovascular diseases, dyslipidemia and metabolic diseases. Despite being key for a healthy metabolism, it is not known how the delivery takes place in the body in molecular level. With our collaborators, we investigate how these lipoproteins interact with the membrane of the cells in our body and how the subsequent delivery takes place. We also investigate the relationship between lipoprotein dynamics in the body and diseases such as ipid storage disorders, obesity, diabetes and metabolic disorders.
Our Collaborators: Birgit Plochberger (Linz)
Key publications: Plochberger et al, Sci Rep, 2017; Axmann et al, Nano Lett, 2019
Biophysics of Wnt Signalling Cellular life is organised by signalling events. Wnt signaling, one of the major signalling pathways, regulates a broad range of biological processes during embryonic development, adult tissue homeostasis and tissue regeneration. Aberrant Wnt signaling is related to various types of cancer, congenital defects and degenerative diseases. Although the late stages of Wnt signalling is extensively studied, the early events at the plasma membrane is less clear. With our collaborators, we investigate how Wnt signalling starts at the plasma membrane. We use advanced imaging as well as biophysical methodologies to address the key aspects of Wnt signalling at the membrane. We particularly focus on the roled of lipid-protein interactions.
Our Collaborators: Gunes Ozhan (Izmir)
Key publications: Sezgin et al, FEBS Jour, 2017; Azbazdar et al, in revision, 2019