Project Details
Projekt
Neuropathic pain resolution by nerve barrier sealing via endogenous netrin-1
Subject Area
Anaesthesiology
Anatomy and Physiology
Anatomy and Physiology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Peripheral nerve injury is accompanied by breakdown of the blood nerve barrier (BNB) and downregulation of tight junction proteins. Self-healing and pain resolution after nerve crush injury is paralleled by resealing of the BNB. However, at which time point resealing occurs and whether this is responsible for reduced hypersensitivity in chronic constriction injury (CCI) of the sciatic nerve or chemotherapy-induced neuropathy is an unsolved issue. This project therefore aims at resolving this dispute by focusing on barrier restoration in neuropathy and pain resolution. The neuronal guidance molecule netrin-1 is barrier-protective in the blood brain barrier, where it upregulates tight junction proteins like claudin-5 and occludin. However, the function of netrin-1 is more complex, because only the full-length netrin-1 is protective, while fragments of netrin-1 have an opposite effect. In this project, we claim that pain resolution in neuropathy is a regulated process caused by nerve barrier sealing by endogenous full-length netrin-1. To this end, we want to accomplish five subprojects in a translational and mechanistic approach. We will first characterize structurally and functionally the restoration of the BNB as well as netrin-1 and its receptors in the resolving neuropathy, e.g. CCI and bortezomib (BTZ)-induced neuropathy (BIPN) (WP 1). Secondly, we will analyze tissue from patients with transient neuropathic pain like complex regional pain syndrome (CRPS) and BIPN regarding barrier proteins and netrin/netrin receptors (WP 2). Finally, we want to booster pain resolution with barrier re-sealing and tight junction protein re-expression using netrin-1 or blockers of its receptors (WP 3). At the same time, electrophysiological properties of the barrier in CCI will be analyzed: ex vivo focusing on the epineurial barrier of the nerve using a specialized impedance Ussing-chamber based system (WP 4) and in vitro focusing on the endoneurial barrier establishing a suitable cell model (WP 5). Here, also the signaling responsible barrier regulation is going to be studied.
DFG Programme
Clinical Research Units
