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

分析紫杉醇引起的皮肤变化可能是 CIPN 的原因

• 批准号: 9181005
• 负责人: Sandra Rieger
• 金额: $ 24.9万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181005
• 关键词: Address; Adult; Adverse effects; Affect; Afferent Neurons; Animals; Area; Axon; Biological Models; Cancer Survivor; Cell Proliferation; Cell division; Cells; Chemotherapy-induced peripheral neuropathy; Clinic; Collaborations; Comparative Study; Cutaneous; Defect; Detection; Devices; Diagnosis; Engineering; Epidermis; Epithelial; Etiology; Fluorescein; Future; Goals; Hand; Human; Image; In Vitro; Individual; Inhibition of Matrix Metalloproteinases Pathway; Injury; Knowledge; Laboratories; Larva; Life; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Microtubules; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Nerve; Nerve Degeneration; Paclitaxel; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Play; Population; Process; Recovery; Research; Role; Sensory; Sensory Nerve Endings; Skin; Stretching; System; Testing; The Jackson Laboratory; Therapeutic; Therapeutic Studies; Time; Translations; Transmission Electron Microscopy; Up-Regulation; Zebrafish; axon injury; axonal degeneration; base; cancer cell; cancer therapy; cell type; chemotherapeutic agent; chemotherapy; collagenase 3; common treatment; disabling symptom; drug development; foot; in vivo; in vivo Model; in vivo imaging; inhibitor/antagonist; injured; interest; keratinocyte; knock-down; malignant breast neoplasm; mouse model; neoplastic cell; prevent; tumor growth

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.

项目概要 该提案旨在研究化疗药物引起的周围神经变性的机制 剂紫杉醇。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，但它也会引起感觉轴突 超过 40% 的人出现退化。受影响最严重的患者需要终止治疗 化疗，这剥夺了他们的全部治疗益处。此外，许多癌症幸存者 持续遭受衰弱症状的困扰，因为恢复可能需要数月至数年的时间。尽管激烈 研究中，我们仍然缺乏关于紫杉醇诱导的外周血管疾病的机制的基础知识 神经病。这种缺乏可能与使用不允许进行全面体内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，例如相互作用 感觉神经末梢与微环境的关系，可能会被排除。研究表明紫杉醇会干扰 具有微管的功能，微管是轴突的主要细胞骨架成分。然而，为什么表皮内 手掌和手足底的感觉神经末梢最初退化的情况尚不清楚。这些皮肤 该区域承受更大的机械应力并且更容易受伤，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引起的周围神经病变。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并发生病理学 先于轴突变​​化的变化。此外，我们还鉴定出基质金属蛋白酶 13 (MMP13) 皮肤中紫杉醇的治疗上有趣的分子靶点。该提案的目标是进一步 使用透射电子显微镜和体内延时表征表皮和轴突变化 成像。此外，我们将确定 MMP13 的细胞类型特异性功能，以确定因果关系 皮肤损伤与轴突变性之间的关系。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，这将为进一步的研究奠定基础 分子研究以及我们的研究成果进入临床。