Analysis of the thrombin pathway in Schwann cells and of its role in peripheral nerve repair and regeneration
Complex nervous systems require rapid nerve impulse transmission. Myelination by Schwann cells (SCs) in the peripheral nervous system (PNS) is essential for efficient saltatory conduction of action potentials.
At the center of the function of myelinated axons are the nodes of Ranvier. In the PNS, nodes are contacted by interdigitating microvilli that project from the end of the SCs to closely appose the nodal axolemma.
On the SC plasma membrane we and others have reported the presence of a protease activated-receptor, PAR1 which is concentrated at the level of the nodes (Shavit et al., 2008; Pompili et al., 2017). This receptor is a sensor for proteases (in particular for thrombin).
In peripheral nerves after injury a rapid rise in thrombin activity can be measured and when this protease is applied to peripheral nerve fibers it determines a conduction block (Shavit et al., 2008; Gera et al., 2016).
Other than PAR1, thrombin can also cut and activate other members of the PAR family. Thus, aim of the present project will be to assess the expression and distribution of the other PAR family members in peripheral nerves. We also aim to analyze how thrombin affects the morphology and function of SCs in sciatic nerve. Our hypothesis is that low levels of thrombin favors nerve repair acting through PAR1 while high concentrations of this protease also activates the other PARs inducing nerve damage and conduction block.
Since there are currently no therapies to effectively protect myelin, or to promote myelin regeneration after PNS injury there is a great need to identify druggable target proteins that are integral regulators governing myelin production.