Research
The Shepherd Lab conducts preclinical research to investigate the mechanisms that link inflammation to the pain induced by various forms of injury, including joint damage and chemotherapy-induced neuropathy, with a particular focus on signaling related to the renin-angiotensin system. The ultimate goal is to identify interventions that can mitigate or prevent the development of pain associated with these chronic disease states.
Tumor-Immune Interactions in Chemotherapy-Induced Peripheral Neuropathy
Our team has shown that mouse models of colorectal cancer develop peripheral neuropathy that is associated with systemic, low-grade inflammation and a pro-thrombotic response. These findings match clinical data. Our current research focuses on modeling the interaction of this "paraneoplastic neuropathy" with cancer treatments, such as oxaliplatin-based chemotherapy.
Left image: Sciatic nerve from an MC38 tumor-bearing mouse showing macrophage infiltration. PGP9.5 nerve fibers are magenta, CD68 macrophages are green, nuclei are blue.
Right image: Transmission electron micrograph of decompacted myelin surrounding an axon in the sciatic nerve of an MC38 tumor-bearing mouse. Magnification: 25,000x.
Angiotensin Peptides (and Downstream Signaling) as Analgesic Targets
In collaboration with Dr. Jelena Janjic at Duquesne University, we are developing macrophage-targeted therapies for neuropathic pain. Such pain is a frequent complication of diabetes or chemotherapy. We have shown that repurposing an angiotensin-converting enzyme inhibitor in a thermoresponsive hydrogel could provide several days of relief from sensory loss in diabetic mice, without introducing common drug side-effects.
In another project in collaboration with Drs. David Tweardy and Cobi Heijnen, we are testing the ability of a STAT3 inhibitor (TTI-101) to relieve chronic neuropathic pain in nerve-injury models.
Image: Section of diabetic mouse hindpaw showing macrophages surrounding a neurovascular bundle. CD68+ macrophages (magenta) co-register with macrophage-targeted nanoparticles loaded with near-infrared fluorescent dye (red). Macrophages surround PGP9.5+ nerve fibers (green). Nuclei: blue.
Fibroblasts Modulate Neuro-Immune Crosstalk to Influence Chronic Pain
PI16 marks a population of steady-state fibroblasts; when deleted, it protects mice from developing chronic pain, at least in part by skewing the phenotype of tissue-resident macrophages to a more pro-resolution, anti-inflammatory phenotype.
Figure showing hindpaw skin 3 days after inflammatory pain was induced by using Complete Freund’s Adjuvant. Left image: Wild-type mouse skin shows abundant infiltration of CD68 macrophages (magenta) but relatively few anti-inflammatory CD206 macrophages (yellow). Right image: PI16 knockout mice do not show pain hypersensitivity at this timepoint. Accordingly, CD68 macrophage infiltration is significantly lower, with a greater abundance of CD206hi (bright yellow) macrophages.