(PQ 9) Dysregulation of epidermal MMP-13 as cause of paclitaxel-induced peripheral neuropathy

项目总结 这项建议试图通过强调紫杉醇诱导的周围神经病变的机制来研究紫杉醇诱导的周围神经病变的机制。 表皮损伤及基质降解酶基质金属蛋白酶13在其中的作用 进程。紫杉醇是一种化疗药物，用于治疗常见的癌症，如肺癌， 乳腺癌和卵巢癌。紫杉醇通过稳定细胞周期阻止肿瘤细胞分裂发挥作用 诱导细胞死亡的微管细胞骨架。紫杉醇的非选择性作用也导致 对健康细胞的损害，导致外周轴突变性(神经病)等副作用。紫杉醇- 大约70%接受化疗的患者会受到周围神经病变的影响。出席的患者有 症状，如麻木、刺痛、温度敏感和疼痛。这些症状的不同在于 严重，但病情最严重的患者必须减少剂量或终止化疗，这 剥夺了他们接受癌症治疗的全部好处，并减少了他们的预期寿命。缺乏 对潜在机制的了解阻碍了有效治疗方法的设计。因为 轴突中含有丰富的微管，一般认为是神经元固有的缺陷，如微管 聚集、异常微管运输和刺激氧化应激的线粒体损伤 促进轴突变性。这些缺陷是轴突变性的原因还是后果尚不清楚。 为了解决这个问题，我的实验室建立了一个斑马鱼体内模型，允许研究 紫杉醇诱导活体动物轴突变性。这些研究表明紫杉醇治疗 增加表皮中基质金属蛋白酶13(MMP13)的活性，导致表皮 损伤和轴突变性。拟议的项目分析了基质金属蛋白酶-13的潜在机制。 表达和功能，因为这种理解将是临床前和临床研究评估的关键 基质金属蛋白酶-13作为治疗紫杉醇所致周围神经病的临床靶点。具体目标1将 探讨稳定的微管和线粒体损伤在氧化应激形成和损伤中的作用 基质金属蛋白酶-13表达。特异性目标2将评估基质金属蛋白酶-13在轴突变性中的作用。此外，在 我们将与梅奥诊所合作，分析紫杉醇治疗的轻度乳腺癌患者的皮肤活检组织，以 检测基质金属蛋白酶-13的表达变化和表皮损伤的可能性。初步数据显示， 紫杉醇诱导角质形成细胞系表达基质金属蛋白酶-13 机制是保守的。本项目的研究结果可能对其他项目也有更广泛的适用性 以氧化应激为标志的神经病，包括由不同的 化疗药物、氟喹诺酮类抗生素和糖尿病。

PROJECT SUMMARY This proposal seeks to examine mechanisms of paclitaxel-induced peripheral neuropathy by emphasizing on epidermal damage and the role of the matrix-degrading enzyme Matrix-metalloproteinase 13 (MMP-13) in this process. Paclitaxel is a chemotherapeutic agent that is used in the treatment of common cancers, such as lung, breast, and ovarian cancer. Paclitaxel functions by arresting tumor cell division through stabilization of the microtubule cytoskeleton, which induces cell death. The non-selective nature of paclitaxel’s action also causes damage to healthy cells, leading to side effects such as peripheral axon degeneration (neuropathy). Paclitaxel- induced peripheral neuropathy affects about 70% of patients undergoing chemotherapy. Patients present with symptoms, such as numbness, tingling, temperature sensitivity and pain. These symptoms differ in their severity but patients that suffer most severely must either reduce the dose or terminate chemotherapy, which deprives them of the full benefits of cancer treatment and decreases their life expectancy. The lack of understanding about the underlying mechanisms has prevented the design of effective treatments. Because microtubules are abundant in axons, it is generally accepted that neuron-intrinsic defects, such as microtubule aggregation, aberrant microtubule transport, and mitochondrial damage that stimulates oxidative stress promote axon degeneration. Whether these defects are a cause or consequence of axon degeneration is unclear. To address this question, my lab established a zebrafish in vivo model that permits studying the dynamics of paclitaxel-induced axon degeneration in the living animal. These studies showed that paclitaxel treatment increases the activity of the matrix-metalloproteinase 13 (MMP-13) in the epidermis, leading to epidermal damage and axon degeneration. The proposed project analyzes the mechanisms underlying MMP-13 expression and function, as this understanding will be critical for pre-clinical and clinical studies assessing MMP-13 as a clinical target in the treatment of paclitaxel-induced peripheral neuropathy. Specific aim 1 will investigate the role of stabilized microtubules and mitochondrial damage in oxidative stress formation and MMP-13 expression. Specific aim 2 will assess the functions of MMP-13 in axon degeneration. In addition, in collaboration with Mayo Clinic we will analyze skin biopsies of paclitaxel-treated mild breast cancer patients to examine MMP-13 expression changes and the potential of epidermal damage. Preliminary data shows that paclitaxel treatment induces MMP-13 expression in a human keratinocyte cell line, indicating that the mechanisms are conserved. The findings in this project may have broader applicability also for other neuropathies in which oxidative stress is a hallmark, including those that are induced by different chemotherapeutic agents, fluoroquinolone antibiotics and diabetes.