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

(PQ 9) 表皮 MMP-13 失调是紫杉醇诱导的周围神经病变的原因

• 批准号: 9305599
• 负责人: Sandra Rieger
• 金额: $ 44.3万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305599
• 关键词: Address; Adhesions; Adverse effects; Affect; Afferent Neurons; Animals; Antibiotics; Axon; Biopsy; Breast Cancer Patient; Cell Adhesion; Cell Death; Cell Line; Cell division; Cells; Clinic; Clinical; Clinical Research; Collaborations; Collagen; Cytoskeleton; Data; Defect; Development; Devices; Diabetes Mellitus; Doctor of Philosophy; Dose; Engineering; Enzymes; Epidermis; Extracellular Matrix; Fluoroquinolones; Functional disorder; Future; Goals; Hand; Histologic; Human; Hydrogen Peroxide; Image; Injury; Intercellular Junctions; Life Expectancy; Malignant neoplasm of lung; Malignant neoplasm of ovary; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Microtubule Stabilization; Microtubule stabilizing agent; Microtubules; Mitochondria; Modeling; Molecular; Motor; Nature; Nerve; Nerve Degeneration; Neurons; Neuropathy; Numbness; Oxidative Stress; Paclitaxel; Pain; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Play; Plus End of the Microtubule; Prevention strategy; Process; Proteins; Reactive Oxygen Species; Research; Resistance; Role; Sampling; Severities; Skin; Source; Specificity; Stretching; Symptoms; Temperature; Testing; Therapeutic; Therapeutic Studies; Tight Junctions; Transmission Electron Microscopy; Tubulin; Up-Regulation; Zebrafish; axonal degeneration; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; clinical application; collagenase 3; common treatment; comparative; design; effective therapy; foot; genetic approach; in vivo; in vivo Model; in vivo imaging; inhibitor/antagonist; keratinocyte; malignant breast neoplasm; neoplastic cell; neurotoxicity; novel; overexpression; pre-clinical; prevent; time use

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.

项目摘要 该建议旨在通过强调以下方面来研究紫杉醇诱导的周围神经病变的机制： 表皮损伤和基质降解酶基质金属蛋白酶13（MMP-13）在其中的作用 过程紫杉醇是一种化疗剂，用于治疗常见癌症，如肺癌， 乳腺癌和卵巢癌。紫杉醇的功能是通过稳定肿瘤细胞的增殖来阻止肿瘤细胞分裂。 微管细胞骨架，其诱导细胞死亡。紫杉醇作用的非选择性性质也导致 损害健康细胞，导致副作用，如外周轴突变性（神经病变）。太平洋- 诱发的周围神经病变影响约70%的接受化疗的患者。患者表现为 症状，如麻木，刺痛，温度敏感和疼痛。这些症状的不同之处在于 严重程度，但患者遭受最严重的必须减少剂量或终止化疗， 剥夺了他们从癌症治疗中获得的全部好处，并缩短了他们的预期寿命。缺乏 对潜在机制的理解阻碍了有效治疗的设计。因为 由于轴突中含有大量的微管，因此通常认为神经元的内在缺陷，如微管， 聚集、异常微管转运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结果尚不清楚。 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，可以研究 紫杉醇诱导的轴突变性。这些研究表明，紫杉醇治疗 增加表皮中基质金属蛋白酶13（MMP-13）的活性，导致表皮 损伤和轴突变性。该项目分析了MMP-13的机制 表达和功能，因为这种理解对于临床前和临床研究评估 MMP-13作为紫杉醇诱导的周围神经病变治疗的临床靶点。具体目标1将 研究稳定微管和线粒体损伤在氧化应激形成中的作用， MMP-13表达。具体目标2将评估MMP-13在轴突变性中的功能。另外在 与马约诊所合作，我们将分析紫杉醇治疗的轻度乳腺癌患者的皮肤活检， 检测MMP-13表达变化和表皮损伤的可能性。初步数据显示， 紫杉醇治疗诱导MMP-13在人角质形成细胞系中的表达，表明紫杉醇治疗诱导MMP-13在人角质形成细胞系中的表达。 机制是保守的。该项目的研究结果可能对其他领域也有更广泛的适用性。 其中氧化应激是标志的神经病，包括由不同的 化疗剂、氟喹诺酮类抗生素和糖尿病。