Functional and metabolic investigation of nociceptive mechanisms underlying pain

and pain resolution in Bortezomib-induced polyneuropathy utilizing a patient-derived in vitro model system

We investigate functional and metabolic mechanisms of pain and its resolution in bortezomib-induced polyneuropathy (BIPN).

Using patient-derived in vitro models, we explore genetic and metabolic determinants of pain persistence and resolution to identify novel therapeutic targets.

Background

Peripheral neuropathy and neuropathic pain are common chemotherapy side effects, severely impacting patients’ health-related quality of life. Bortezomib (BTZ), a proteasome inhibitor used as a first-line treatment for multiple myeloma, often induces painful neuropathy, which resolves in some but persists in others. The mechanisms governing pain resolution remain unclear. Genetic polymorphisms (rs2839629, rs915854) have been linked to pain outcomes, yet their pathophysiological role requires further investigation

Research Objective

We use induced pluripotent stem cells (iPSCs) derived from multiple myeloma patients with or without painful BIPN to:

Investigate the impact of rs2839629 and rs915854 polymorphisms on pain persistence and resolution,
Analyze sensory neuron-Schwann cell interactions in BIPN-associated nociception using 2D mono- and co-culture systems,
Employ CRISPR/Cas9 gene editing to generate isogenic control lines for mechanistic studies,
Conduct transcriptomic and electrophysiological analyses to identify druggable targets,
Assess metabolic alterations associated with neuropathic pain using Seahorse Analyzer technology.

Significance

This project advances the understanding of neuropathic pain mechanisms and identifies druggable targets for pain prevention and resolution in BIPN. Combining patient-derived cellular models with functional and metabolic analyses, the study lays the foundation for personalized therapeutic strategies to alleviate chemotherapy-induced neuropathic pain and improve patient outcomes.

Research Team NP2

Principal investigators

Univ.-Prof. Dr. Nurcan Üçeyler, MD, MHBA
Chief Physician Consultant, Department of Neurology
University Hospital Würzburg

Dr. Julia Neubauer
Managing Director
Fraunhofer Project Center for Stem Cell Process Engineering Würzburg

Members of the team

Dr. Eva Meller, MD, Clinician Scientist

Dr. Magnus Schindehütte, MD, Clinician Scientist

Dr. Simon Weiner, MD, Clinician Scientist

Annsophie Amann, PhD Student

Selected publications

Ammoun S, Ristic N, Matthies C, Hilton DA, Hanemann CO (2010)
Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244
Neurobiol Dis. 2010; 37: 141-6
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Breun M, Nickl R, Perez J, Hagen R, Lohr M, Vince G, Matthies C (2019)
Vestibular Schwannoma Resection in a Consecutive Series of 502 Cases via the Retrosigmoid Approach: Technical Aspects, Complications, and Functional Outcome.
World Neurosurg. 2019; 129: e114-e27
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Pham M, Oikonomou D, Hornung B, Weiler M, Heiland S, Baumer P, Kollmer J, Nawroth P, Bendszus M (2015)
Magnetic resonance neurography detects diabetic neuropathy early and with Proximal Predominance
Ann Neurol. 2015; 78: 939-48
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Üçeyler N, Schäfer KA, Mackenrodt D, Sommer C, Müllges W (2016)
High-Resolution Ultrasonography of the Superficial Peroneal Motor and Sural Sensory Nerves May Be a Non-invasive Approach to the Diagnosis of Vasculitic Neuropathy.
Front Neurol. 2016; 7: 48
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