Analyzing paclitaxel-induced changes in the skin as possible cause of CIPN

项目总结 本研究旨在探讨化疗所致周围神经变性的机制。 紫杉醇探员。紫杉醇用于治疗常见癌症，如乳腺癌、卵巢癌和肺癌。 虽然紫杉醇阻止癌细胞分裂，从而干扰肿瘤生长，但它也导致感觉神经轴突 超过40%的个体退化。受影响最严重的患者需要终止 化疗，这剥夺了他们的全部治疗利益。此外，许多癌症幸存者 持续遭受衰弱症状，因为恢复可能需要几个月到几年的时间。尽管紧张 研究表明，我们仍然缺乏关于紫杉醇诱导外周血的机制的基础知识 神经病。这种缺乏可能与使用不允许进行全面活体分析的模型系统有关。 因此，发现可能导致这种情况的重要过程，例如 感觉神经末梢与微环境，可能是排除的。已有研究表明，紫杉醇对 随着微管的作用，轴突的主要细胞骨架成分。然而，为什么要在表皮内 手掌和脚底的感觉神经末梢最初退化尚不清楚。这些衣服里的皮肤 这些区域承受的机械应力增加，受伤更频繁，这可能在 这种情况的病因学。为了评估这一点，我的实验室在斑马鱼身上建立了一个独特的模型系统 允许对紫杉醇引起的活体动物周围神经病变进行分析。使用这种活体模型的研究 提示表皮角质形成细胞对紫杉醇治疗高度敏感，并经历病理变化。 轴突中先于这些变化的变化。此外，我们还鉴定了基质金属蛋白酶13(MMP13)是一种 皮肤中具有治疗意义的紫杉醇分子靶点。这项提议的目标是进一步 用透射电子显微镜和活体时间推移技术表征表皮和轴突的变化 成像。此外，我们将确定MMP13的细胞类型特异性功能，以建立因果关系 皮肤损伤与轴突变性的关系。我们还将评估表皮和MMP13的作用 在紫杉醇诱导的小鼠周围神经病变模型中，这将为进一步 分子研究和我们的研究成果进入临床的进展。

PROJECT SUMMARY 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.