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Dissertation
From biomarkers to bench: identification of a therapeutically targetable resident memory T cell population in a mouse model of complex regional pain syndrome
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2024
DOI:
https://doi.org/10.17918/00010591
Abstract
Complex regional pain syndrome (CRPS) is a chronic pain disorder that is most often brought on by acute trauma such as fracture and lacks diagnostic biomarkers and approved treatments. Here, we extend our prior studies that establish microRNA (miRNA) as potential biomarkers in individuals with CRPS and identify miRNA that share dysregulation in the mouse tibia fracture model (TFM) of CRPS. We show miR-25, commonly dysregulated in CRPS and TFM, is capable of regulating T cell activation marker CD69 in Jurkat T cells. We build upon prior work that has identified local and systemic autoimmune mechanisms underlying CRPS etiology and identify a population of T cells in the skin of TFM mice in which CD69 is persistently upregulated. These resident memory T cells (TRM) include CD8+ and CD4+ populations that reside in distinct environments in the epidermis and dermis. Using fingolimod, an inhibitor of lymphocyte migration, we show that nociceptive sensitization does not depend on circulating T cells. By phenotyping TRM populations across TFM development we identify that CD49a expression defines distinct populations of TRM. CD49a- TRM increase during the acute stage of the model, whereas CD49a+ TRM increase as the model resolves. Using Nur77-GFP mice to report in vivo antigen dependent T cell activation, we demonstrate that CD49a- TRM display increased autoreactivity in the skin of TFM mice. Seeking to bridge back to patients, we demonstrate that tofacitinib , an FDA approved janus kinase inhibitor, is capable of downregulating TRM activity and TNF𝛼 release while reducing nociceptive sensitization, offering new potential therapies for Individuals with CRPS.
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Details
- Title
- From biomarkers to bench
- Creators
- Jason Wickman
- Contributors
- Seena Ajit (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 203 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021902013804721