This proposal seeks to examine mechanisms of peripheral nerve degeneration induced by the chemotherapeutic agent paclitaxel. Paclitaxel is used in the treatment of common cancers, such as breast, ovarian and lung cancer. While paclitaxel arrests cancer cell division and thus interferes with tumor growth, it also causes sensory axon degeneration in greater than 40 percent of individuals. Patients that are most severely affected need to terminate chemotherapy, which deprives them of the full treatment benefits. Moreover, many cancer survivors continuously suffer from the debilitating symptoms since the recovery may take months to years. Despite intense research, we still lack fundamental knowledge about the mechanisms leading to paclitaxel-induced peripheral neuropathy. This lack may relate to the use of model systems that do not permit comprehensive in vivo analyses. Therefore the discovery of important processes that may contribute to this condition, such as interactions of sensory nerve endings with the microenvironment, may be precluded. It has been shown that paclitaxel interferes with the function of microtubules, the major cytoskeletal components of axons. However, why intra-epidermal sensory nerve endings in the palm and sole of hands and feet initially degenerate is unclear. The skin in these areas withstands increased mechanical stress and is more frequently injured, which may play a role in the etiology of this condition. To assess this, my laboratory has established a unique model system in zebrafish that permits the analysis of paclitaxel-induced peripheral neuropathy in live animals. Studies using this in vivo model suggest that epidermal keratinocytes are highly susceptible to paclitaxel treatment and undergo pathological changes that precede those in axons. We moreover identified matrix-metalloproteinase 13 (MMP13) as a therapeutically interesting molecular target of paclitaxel in the skin. The goal of this proposal is to further characterize epidermal and axonal changes using transmission electron microscopy and in vivo time-lapse imaging. In addition, we will determine cell type-specific functions of MMP13 to establish the cause-and-effect relationship between skin damage and axon degeneration. We will also assess the role of epidermis and MMP13 in a mouse model of paclitaxel-induced peripheral neuropathy, which will lay the groundwork for further molecular studies and the advancement of our findings into the clinic.
This research seeks to explore biomechanisms of paclitaxel-induced peripheral neuropathy, a condition of nerve damage, emphasizing on epithelial damage as possible underlying cause. These comparative studies in zebrafish and mice will lay the groundwork for further molecular characterizations and drug development studies.
|Waldron, Ashley L; Schroder, Patricia A; Bourgon, Kelly L et al. (2018) Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity. J Diabetes Complications 32:249-257|
|Lisse, Thomas S; Middleton, Leah J; Pellegrini, Adriana D et al. (2016) Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Proc Natl Acad Sci U S A 113:E2189-98|