Dysregulation of epidermal MMP-13 as cause of paclitaxel-inducedperipheral neuropathy

表皮 MMP-13 失调是紫杉醇诱导的周围神经病变的原因

基本信息

批准号：
10198857
负责人：
Sandra Rieger
金额：
$ 31.03万
依托单位：
UNIVERSITY OF MIAMI CORAL GABLES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198857
关键词：
Address Adhesions 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 Future Goals Hand Histologic Human Hydrogen Peroxide Image Injury Intercellular Junctions Life Expectancy Malignant Neoplasms 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 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 mitochondrial dysfunction neoplastic cell nerve damage neurotoxicity novel overexpression preclinical study prevent side effect time use

项目摘要

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紫杉醇引起的周围神经病的机制表皮损伤和基质降解酶基质基质蛋白酶13（MMP-13）的作用过程。紫杉醇是一种化学治疗剂，用于治疗常见癌症，例如肺部，乳腺癌和卵巢癌。紫杉醇通过稳定来阻止肿瘤细胞分裂来发挥作用微管细胞骨架，诱导细胞死亡。紫杉醇动作的非选择性也导致对健康细胞的损害，导致副作用，例如外周轴突变性（神经病）。紫杉醇 - 诱导的周围神经病会影响约70％的接受化学疗法的患者。患者在场症状，例如麻木，刺痛，温度敏感性和疼痛。这些症状有所不同严重程度但是遭受最严重的患者必须降低剂量或终止化疗，这剥夺了他们的全部癌症治疗益处，并降低了他们的预期寿命。缺乏了解基本机制已阻止了有效治疗的设计。因为微管在轴突中很丰富，普遍认为神经内在缺陷，例如微管聚集，异常的微管转运和线粒体损伤，刺激氧化应激促进轴突变性。这些缺陷是否是轴突变性的原因或结果尚不清楚。为了解决这个问题，我的实验室建立了一个斑马鱼在体内模型中，允许研究动态紫杉醇引起的活动物中的轴突变性。这些研究表明紫杉醇治疗增加表皮中基质 - 甲基蛋白酶13（MMP-13）的活性，导致表皮损伤和轴突变性。拟议的项目分析了MMP-13的基础机制表达和功能，因为这种理解对于评估临床前和临床研究至关重要 MMP-13是治疗紫杉醇诱导的周围神经病的临床靶标。具体目标1将研究稳定的微管和线粒体损伤在氧化应激形成中的作用和 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，在与梅奥诊所的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查MMP-13表达变化和表皮损伤的潜力。初步数据表明紫杉醇治疗在人角质形成细胞系中诱导MMP-13的表达，表明机制是保守的。该项目中的发现可能也更广泛地适用于其他氧化应激是标志的神经病，包括那些由不同的诱导的神经病化学治疗剂，氟喹诺酮抗生素和糖尿病。