Project Details
Projekt
Modelling barrier resealing of blood‐peripheral nerve and blood‐DRG barriers for pain resolution in nerve injury and complex regional pain syndrome (CRPS)
Applicants
Privatdozentin Dr. Susanne Marlen Krug; Professorin Dr. Heike Lydia Rittner; Dr. Magnus Schindehütte
Subject Area
Molecular and Cellular Neurology and Neuropathology
Anaesthesiology
Anatomy and Physiology
Anaesthesiology
Anatomy and Physiology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Peripheral nerve injury is associated with disruption of the blood‐nerve barrier (BNB). In FP1, we thoroughly characterized the exact timing of pain and its resolution, its spatial transcriptomic signature, and neuronal barrier leakage and resealing after chronic constriction injury (CCI) or bortezomib‐induced neuropathy (BIPN). Barrier damage is worse in CCI and affects all barriers; in BIPN only the perineurial barrier is leaky. Capillary leakage and closure for large‐ to medium‐sized proteins parallels pain and its resolution. Similarly, the vasculature and CLDN5 are affected in skin biopsies of patients with acute complex regional pain syndrome (CRPS). In the dorsal root ganglion (DRG) imaging pilot experiments increased neuronal activity in response to electrical stimulation and increased barrier leakiness in a subset of patients was observed. We identified two pathways accelerating barrier resealing and pain resolution: local application of the neuronal guidance molecule netrin‐1 and resolvin D1 (RvD1), a specialized pro‐resolving mediator (SPMs). Both reseal the capillary barrier for fibrinogen and/or the myelin and perineurial barrier. Fibrinogen removal is further supported by degrading enzymes and resolution‐type macrophages. To mechanistically understand and translate these networks and their different cellular compartments, we now want to study our findings in ex vivo rodent and human models and extend our barrier research to the barrier of the DRG. The first two subprojects will define the cellular ensemble and pathways of barrier‐resealing of the perineurial (WP1) and endoneurial barriers (WP2) as part of the whole BNB using rat and human nerve samples and primary cell cultures to generate multicellular models reflecting the BNB. WP3 will spatiotemporally map the blood‐DRG barrier with endothelial cells and CD163+ macrophages after nerve injury, pharmacologically restore the barrier, and resolve pain using the above‐men‐ tioned pathways. WP4 will study neurovascular coupling of the affected DRG in vivo in patients with CRPS patients during pain resolution versus persistence by the novel imaging technique of functional DRG fMRI. In summary, the results will help to design pain resolution therapies by local resealing or even drug delivery therapies and improve MRI diagnostics and outcome prediction for nerve injury and CRPS.
DFG Programme
Clinical Research Units
