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In vitro and in vivo imaging in the field of dermatology. Discovery and knowledge through collaboration.
The functional and anatomical relationships among primary afferent fibers, blood vessels, and cancers are poorly understood, though recent evidence suggests that physical and biochemical interactions between these peripheral components are important to both tumor biology and cancer-associated pain.
· To this end we introduced the Discoma coral-derived red fluorescent protein (DsRed2) into the NCTC 2472 fibrosarcoma line using the Sleeping Beauty (SB) transposon methodology and implanted these DsRed2 fibrosarcoma cells into the calcaneous bone of a mouse in a cancer pain model developed by Paul Wacnik and George Wilcox. This cancer pain model uniquely allows visualization of tumor-nerve-vessel associations in context with behavioral assessment of tumor-associated hyperalgesia. Results describe for the first time the interaction among sensory nerves, blood vessels, and tumor cells in otherwise healthy tissue and support the hypothesis that direct tumor cell-axon communication may underlie, at least in part, the occurrence of cancer pain.
· We are currently conducting a pilot study wherein we can visualize, quantify, and test biochemical interactions and pain behaviors in the periphery at the tumor site in an intra-vital imaging model of cancer pain and tumor growth. DsRed2 fibrosarcoma cells are implanted into mice expressing Yellow Fluorescent Protein-tagged nerves and fluorescent nano-crystals, emitting in the near IR, are injected into the tail vein to visualize the vasculature. Under anesthesia these fluorescent markers are visualized using multiphoton scanning microscopy. We expect to determine the contribution of regional/local soluble factors to cancer pain and tumor growth. Understanding the contributions of nerves and signaling molecules in and around tumors will provide direction into the development of more effective analgesic modalities and possibly the development of new strategies to inhibit tumor growth and/or metastasis that may be mediated by neuronal components.
· I am working with Darryl Hamamoto, a member of the Pain Center, to study the analgesic capacity of cannabinoids in the DsRed2-transfected murine cancer model.
· Working with researchers, Ann Bode and Zigang Dong of the Hormel Institute, we are examining the role of vanniloid compounds in a chemically-induced skin tumor mouse model. Experiments are in progress to visualize, by multi-labeling and confocal microscopy, interactions of important mediators in the signal transduction cascade of this skin cancer model. Work with topical gingerol, as a photo-protective agent in a mouse model., have also been initiated.
· A collaborative effort between Neurology (Bill Kennedy, Mona Selim, and Gwen Crabb), Neuroscience (George Wilcox) and Dermatology (Marna Ericson, Maria Hordinsky, Habib BenelHabib) was initiated by Anne Bertelson, a neurologist/pain specialist from Norway. We will be investigating neural/immune interactions in patients with peripheral neuropathies. Dr. Bertelson has spent some time here at Minnesota learning techniques of multi-labeling and visualization of neuronal structures, vasculature, and immune cells in human.
· Patty Tam, a researcher in Rheumatology, and I have initiated an analysis on pain in a viral-induced myopathy mouse model, developed in Dr. Tam’s lab, that mimics chronic fatigue syndrome.
· With funding from Guilford Pharmaceuticals we are exploring neuronal aspects of the hair growth cycle using topically applied neurotrophic compounds, i.e. neuroimmunophilin ligand analogs, in a mouse model. Using stereology, we are quantifying the effects of the neuroimmunophilin ligand analogs on epidermal and perifollicular nerve length.
· Working with Maria Hordinsky in dermatology we have examined neural and immune aspects of hair growth, itch, and pain in human skin. This work has been presented internationally and in publication format. A manuscript is currently in preparation on a collaborative project with Jeff Lander and Whitney Tope examining nerve/tumor interactions from excised human skin cancers.
· Dr. Tam and I are pursing the study of using second harmonic generation emission for live non-invasive imaging of Collagen II in mouse knee joints.
· Collaborative efforts with Uli Munderloh, Mike Herron, Tim Kurtii from the U of MN entomology department and Jesse Goodman of the FDA on the tick born infection of microvascular endothelium by Anaplasma phagocytophilum have led to a fruitful collaboration. See: U of MN News Release: Researchers Take Aim At Tick-Borne Disease With $2.8 Million NIH Grant.
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