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Tissue repair is an intricate process, which requires the coordinated interactions between various cell types in the wound. The small reactive oxygen species hydrogen peroxide (H2O2) plays an important role in wound repair by functioning as a pleiotropic signaling molecule to attract leukocytes toward the site of injury, by promoting angiogenesis, and by stimulating cutaneous sensory axon regeneration (Rieger & Sagasti, PLoS Biology 2011). We are particularly interested in the mechanisms of H2O2 signaling during wound repair. In addition, we have developed a zebrafish model for studying mechanisms of paclitaxel-induced peripheral neuropathy in the living animal using in vivo imaging. Paclitaxel is a chemotherapeutic agent that is widely used in the treatment of breast, ovarian and lung cancer. It has been shown that up to 97% of patients treated with paclitaxel develop symptoms such as numbness, tingling and pain. While many patients recover, those that are most severely affected (~30%) must terminate chemotherapy or reduce the dose, which deprives them of the full benefits of cancer treatment. The mechanisms underlying this condition are unclear and hence there are no effective treatments available. We hope that our research will contribute to the development of therapeutics. By utilizing the knowledge gained from axon regeneration studies, we have been able to identify a new drug target that shows promising results in the treatment of paclitaxel-induced peripheral neuropathy in zebrafish.
Project 1: Define the molecular mechanisms that promote injury-induced cutaneous axon regeneration
Injury-induced cutaneous axon regeneration is conserved among vertebrates but despite this conservation, we do not yet fully understand the basic mechanisms underlying this process. We are exploring in particular the role of H2O2 and its downstream targets in promoting cutaneous axon repair. We previously showed that cutaneous axon regeneration critically depends on H2O2 that is released from keratinocytes after injury. Identifying and analyzing the function of H2O2 and its targets will be critical for developing strategies that promote axon growth under pathological conditions, such as peripheral neuropathy disorders. We are utilizing genetically accessible and optically clear zebrafish larvae to assess the interactions between cutaneous axons and wound keratinocytes in live animals. We have already identified several interesting H2O2-dependent molecules using RNA sequencing and begun to vigorously dissect the molecular mechanisms leading to cutaneous axon regeneration. Our studies point to a parallel signaling function of H2O2 in keratinocytes and somatosensory neurons, both of which are essential for axon regeneration.
Project 2: Delineate the role of epidermis in paclitaxel-induced peripheral neuropathy
We developed a zebrafish in vivo model to analyze mechanisms of paclitaxel–induced axon degeneration and impaired regeneration in live zebrafish (Lisse et al., PNAS 2016). This model revealed that the epidermis undergoes rapid phenotypic changes upon paclitaxel-treatment prior to the onset of axon degeneration. These changes correlate with upregulation of the collagen-degrading matrix metalloproteinase, MMP-13, in epidermal keratinocytes. Excitingly, co-administration of paclitaxel and two MMP-13 inhibitory compounds show significant beneficial effects (patent pending), suggesting that increased MMP-13 activity and matrix degradation in the epidermis underlies paclitaxel neurotoxicity. A common view is that paclitaxel causes neurotoxicity by axon-specific microtubule stabilization leading to microtubule transport defects and mitochondrial damage. We argue that not axons but rather keratinocytes are the primary targets of paclitaxel in the etiology of paclitaxel-induced peripheral neuropathy. We are currently exploring this idea. We are also collaborating with clinical investigators to further explore the role of MMP-13 in human paclitaxel-treated patients.
Project 3: Identify sensory axon-dependent wound repair mechanisms
Successful wound repair depends on the regeneration of cutaneous sensory axons since these secrete pro-inflammatory peptides that promote healing. Evidence suggests that denervation of wounds delays healing and promotes chronic wound formation due to effects on keratinocyte migration. We have established a larval zebrafish in vivo model to analyze this in more detail via time-lapse imaging.