Chronic Chemotherapy Peripheral Neuropathy: Role of Neuroplasticity and Stress

慢性化疗周围神经病变：神经可塑性和压力的作用

• 批准号: 10472499
• 负责人: JON DAVID LEVINE
• 金额: $ 64.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472499
• 关键词: Chronic; Neuronal Plasticity; Peripheral Nervous System Diseases; Role; Stress; chemotherapy

The premise of this research project is that nociceptor neuroplasticity is an important mechanism underlying chronic chemotherapy-induced peripheral neuropathy (CIPN) and that stress plays a key role in the induction of this neuroplasticity. In this grant, we will evaluate the role of nociceptor neuroplasticity in chronic CIPN induced by two clinically important classes of cancer chemotherapy (CTX), i.e., platinum and taxane compounds. Experiments will evaluate the role of diverse stressors (i.e., CTX administration, early life stress, adult chronic stress, prior to, during or after CTX), drugs used to treat co-morbid medical conditions that also act on stress axis mediator receptors (i.e., glucocorticoid and catecholamine), as well as resilience (i.e., resistance to stress) on the development of chronic CIPN. In addition, we will study neuroplasticity and stress in two other clinically important features of chronic CIPN that remain poorly understood: 1) platinum-induced cold allodynia and 2) “coasting” (i.e., worsening of CIPN after stopping CTX). Finally, we will harvest dorsal root ganglia (DRG), as well as blood, from rats exposed to CTX and stress to evaluate changes in gene expression in blood and the peripheral nervous system. These analyses will allow us to better identify risk factors for, and potential mechanisms of, chronic CIPN and could be used to help interpret future clinical studies to identify patients’ susceptibility for development of CIPN. The results of the proposed preclinical experiments have important clinical implications, including: 1) increased knowledge of the role of mechanisms of neuroplasticity underlying chronic CIPN that could identify new therapeutic targets to prevent and treat chronic CIPN; 2) increased understanding of how neuroendocrine stress axis mediators, acting at their cognate receptors on sensory neurons, contribute to chronic CIPN; 3) understanding mechanisms responsible for loss of efficacy of opioid analgesics in CIPN and its relationship to induction of nociceptor neuroplasticity; 4) understanding the mechanism of oxaliplatin-induced cold allodynia; 5) determining if tapering instead of stopping CTX mitigates coasting; and 6) elucidate genomic biomarkers for the development of chronic CIPN.

该研究项目的前提是伤害感受器的神经塑性是慢性化学疗法诱导的周围神经病（CIPN）的重要机制，并且压力在诱导这种神经塑性中起着关键作用。在这笔赠款中，我们将评估伤害感受器神经可塑性在两种临床上重要的癌症化学疗法（CTX）诱导的慢性CIPN中的作用，即铂和紫杉烷化合物。 Experiments will evaluate the role of divergent stresses (i.e., CTX administration, early life stress, adult chronic stress, prior to, during or after CTX), drugs used to treat co-morbid medical conditions that also act on stress axis mediator receptors (i.e., glucocorticoid and catecholamine), as well as resilience (i.e., resistance to stress) on the development of chronic CIPN.此外，我们将研究慢性CIPN的另外两个临床重要特征的神经质性和压力，这些特征保持不足：1）铂诱导的冷异质症和2）“沿海”（即停止CTX后的CIPN）。最后，我们将从暴露于CTX的大鼠和压力中收获背根神经节（DRG）以及血液，以评估血液和周围神经系统中基因表达的变化。这些分析将使我们能够更好地识别慢性CIPN的危险因素和潜在机制，并可用于帮助解释未来的临床研究，以鉴定患者对CIPN发育的敏感性。所提出的临床前实验的结果具有重要的临床意义，包括：1）对慢性CIPN基础神经可塑性机制的作用的知识增加，这些慢性CIPN可以确定可以鉴定出可预防和治疗慢性CIPN的新治疗靶标的； 2）对神经内分泌应力轴介质在感觉神经元上作用于其同源受体如何有助于慢性CIPN的神经内分泌应激轴介质如何增加理解。 3）理解导致阿片类镇痛药在CIPN中有效性丧失的机制及其与伤害感受器神经可塑性的关系； 4）了解奥沙利铂诱导的冷异常动物症的机制； 5）确定逐渐减少而不是停止CTX会减轻沿海的速度；和6）阐明基因组生物标志物用于慢性CIPN的发展。