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，伤害感受器神经可塑性是慢性化疗引起的周围神经病变（CIPN）的重要机制，而压力在诱导这种神经可塑性中起着关键作用。在这笔资助中，我们将评估伤害感受器神经可塑性在由两类临床上重要的癌症化疗（CTX）（即铂和紫杉烷化合物）诱导的慢性 CIPN 中的作用。实验将评估不同压力源（即 CTX 给药、早期生活压力、成人慢性压力、CTX 之前、期间或之后）、用于治疗同时作用于压力轴介质受体（即糖皮质激素和儿茶酚胺）的共病医疗状况的药物，以及对慢性 CIPN 发展的恢复力（即对压力的抵抗力）的作用。此外，我们将研究慢性 CIPN 的另外两个临床重要特征的神经可塑性和应激，这些特征仍知之甚少：1）铂引起的冷异常性疼痛和 2）“滑行”（即停止 CTX 后 CIPN 恶化）。最后，我们将从暴露于 CTX 和应激的大鼠身上采集背根神经节 (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确定慢性 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，以确定患者发生 CIPN 的易感性。所提出的临床前实验的结果具有重要的临床意义，包括：1）增加了对慢性 CIPN 背后的神经可塑性机制的作用的了解，可以确定预防和治疗慢性 CIPN 的新治疗靶点； 2) 加深对神经内分泌应激轴介质作用于感觉神经元上的同源受体如何导致慢性 CIPN 的了解； 3) 了解 CIPN 中阿片类镇痛药失效的机制及其与伤害感受器神经可塑性诱导的关系； 4）了解奥沙利铂引起冷异常性疼痛的机制； 5) 确定逐渐减少而不是停止 CTX 是否可以缓解滑行； 6) 阐明慢性 CIPN 发展的基因组生物标志物。