Project Details
Projekt
Structural and molecular basis of pain and resolution in genetically determined neuropathies
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426503586
Neuropathic pain is a cardinal symptom in patients with polyneuropathy of neurofibromatosis type 1, 2, and 3 (NF1, NF2, NF3). Pain occurs even in the absence of macroscopic tumors and it may resolve over time even in the presence of a considerable tumor load. The pathophysiology of NF-pain and pain resolution is unknown. We found that peripheral neuropathy in some patients may be treated by microsurgical nerve decompression via complete resection or reduction of macroscopic tumor load followed by subsequent pain resolution. We further found an association between NF-neuropathy and surgically untreatable non-tumorous disseminated nerve fascicle microlesions. These were quantified by MR-neurography which allows large anatomical coverage and microstructural resolution of nerve fascicles. Furthermore, we developed MRI techniques for high-resolution structural and functional imaging of dorsal root ganglia (DRG) at the lumbo-sacral level. Using DRG imaging, we found non-tumorous DRG enlargement in NF2 as another disease specific alteration discriminating NF2 accurately from NF3. Using specialized clinical, electrophysiological, and histological tests, we characterized small nerve fiber pathology in pain disorders and succeeded in generating in vitro test systems based on patient-derived sensory neurons via pluripotent stem cells. In schwannomas of NF patients, we found higher levels of the chemokine receptor CXCR4 compared to non-NF schwannomas and to healthy nerves, and a strong correlation with functional neuropathy indicating the importance of CXCR4 for invasive activity at the tumor-nerve interface. We hypothesize that NF-associated neuropathic pain occurs and develops in a disease-specific manner across the spectrum of NF disorders. We postulate that variability in pain resolution, with and without treatment, is associated with non-tumorous microlesions at the post-ganglionic level and pathomorphological or functional alterations at DRG level. We further hypothesize specific genetically determined alterations at the sites of predominant post-ganglionic or ganglionic structural and functional injury. Our aims are 1) To determine morphological parameters as potential surrogate markers for pain and pain resolution in NF1, NF2, and NF3 combining deep clinical phenotyping with a comprehensive high-resolution imaging approach; 2) to decipher the molecular mechanisms of pain development, persistence, and resolution in NF via a personalized approach, investigating differences in Schwann cell activities and electrophysiological characteristics of patient-derived sensory neurons and Schwann cells. Our project combines deep clinical phenotyping with novel high-resolution nerve imaging techniques and cutting-edge cellular, molecular, and electrophysiological methodology. We seek to set up clinically useful surrogate markers for pain and pain resolution in NF patients and to decipher the molecular mechanisms underlying pain resolution in NF.
DFG Programme
Clinical Research Units
