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

项目摘要 该建议旨在研究化疗药物诱导的周围神经变性的机制， 紫杉醇制剂。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， 超过40%的个体会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效益。此外，许多癌症幸存者 持续遭受衰弱的症状，因为恢复可能需要数月至数年。尽管激烈 尽管有大量的研究，但我们仍然缺乏关于导致紫杉醇诱导的外周血淋巴细胞凋亡的机制的基础知识。 神经病变这种缺乏可能与使用的模型系统，不允许全面的体内分析。 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之间的联系可能会被排除。已经表明紫杉醇干扰 具有微管的功能，微管是轴突的主要细胞骨架成分。但是，为什么表皮内 感觉神经末梢在手掌和脚底的手和脚最初退化是不清楚的。这里面的皮肤 区域承受增加的机械应力并且更频繁地受伤，这可能在 这种情况的病因。为了评估这一点，我的实验室在斑马鱼中建立了一个独特的模型系统， 允许在活体动物中分析紫杉醇诱导的周围神经病变。使用该体内模型的研究 表明表皮角质形成细胞对紫杉醇治疗高度敏感， 在轴突之前发生的变化。此外，我们还鉴定了基质金属蛋白酶13（MMP 13）作为 紫杉醇在皮肤中的治疗上令人感兴趣的分子靶点。该提案的目的是进一步 使用透射电子显微镜和体内时间推移表征表皮和轴突变化 显像此外，我们将确定MMP 13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。 在紫杉醇诱导的周围神经病变的小鼠模型中，这将为进一步研究奠定基础。 分子研究和我们的发现在临床上的进展。

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.