Novel Path to Chronic Sensorimotor Dysfunction and Treatment for Chemotherapy

慢性感觉运动障碍和化疗治疗的新途径

• 批准号: 9609022
• 负责人: Timothy C Cope
• 金额: $ 31.83万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9609022
• 关键词: Acute; Adopted; Adverse effects; Afferent Neurons; Aftercare; Antineoplastic Agents; Back; Behavior; Biophysical Process; Biophysics; Cancer Model; Chemotherapy-induced peripheral neuropathy; Chronic; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Computer Simulation; Data; Defect; Development; Electrophysiology (science); Esthesia; FDA approved; Failure; Fatigue; Functional disorder; Gene Expression; Generations; Immunohistochemistry; Impairment; Inflammatory; Injections; Lead; Malignant Neoplasms; Measurement; Measures; Mechanoreceptors; Membrane; Modeling; Molecular; Motor Neurons; Nerve Degeneration; Nervous system structure; Neuronal Dysfunction; Neurons; Neuropathy; Outcome; Pain; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacology; Play; Process; Publishing; Rattus; Regimen; Reporting; Research; Research Support; Role; Secure; Sensorimotor functions; Sensory; Sensory Disorders; Serotonin Agonists; Signal Pathway; Sodium; Specificity; Symptoms; Testing; Time; Tissues; Translating; Work; afferent nerve; axonal degeneration; biophysical properties; chemotherapy; clinically relevant; design; differential expression; disability; disabling symptom; experimental group; experimental study; follow-up; functional disability; improved; in vivo; mRNA Expression; meetings; neuronal excitability; neurotransmission; novel; oxaliplatin; pre-clinical; relating to nervous system; response; restoration; standard of care; success; targeted treatment; therapy development

Abstract Chemotherapy is often accompanied by neuropathic sensory disorders that can limit or end treatment and cause long-term disability. Current research supports axon degeneration and hyperexcitability as underlying mechanisms. However, our recent research reveals an additional, absolutely novel mechanism having the potential to account for loss of patient function in chemotherapy-related neuropathy. We obtained in vivo electrophysiological measures which showed functional impairment of neuronal signaling from sensory and motor neurons in rats several weeks after receiving a clinically-relevant regimen of oxaliplatin (OX) chemotherapy. Hypo-excitability was consistently expressed as conspicuous failure to sustain firing in response to fixed levels of stimulation. The specificity of this defect, which leaves transient firing unaffected, suggests that OX treatment may impair sodium persistent inward currents (NaPIC) in sensory and motor neurons. Recent findings published in our lab promote this notion by showing that pharmacological block of NaPIC mimics the effect of OX on sustained firing. While our findings isolate chronic effects of chemotherapy on neuronal excitability, there is no chemotherapy without cancer. Cancer and OX therapy may act synergistically on common signaling pathways (e.g. oxidative and inflammatory) to produce neuronal hypo- excitability. The possibility of an interaction between cancer and OX therapy gains excitement from our preliminary reports that discovered sensory and motor neuron hypo-excitability is significantly amplified in rats with colorectal cancer. Here we propose incisive tests of our working hypothesis that OX treatment chronically impairs static neuronal signaling by reducing NaPIC in a rat model of cancer. We will measure the firing behavior of sensory and motor neurons via in vivo electrophysiological studies of cancer rats treated with OX, in order to achieve the following four specific aims: 1) test the hypothesis that interactions with cancer-related processes exacerbate chemotherapy-induced hypo-excitability in sensory and motor neurons; 2) test the hypothesis that chronic defects in repetitive firing by motor neurons result from an OX-induced decrease in persistent inward current; 3) develop therapy that normalizes firing of sensory and motor neurons in rats treated for cancer with OX; 4) identify factors related to the development of hypo-excitability induced by OX in a rat model of colorectal cancer. Successful accomplishment of these studies will: 1) determine for the first time in the CIPN field, of the extent to which chronic deficits in neuronal excitability arise from OX therapy, colorectal cancer, and their combination; 2) identify biophysical mechanisms underlying firing deficits of a CNS neuron after OX treatment; 3) develop pre-clinically a viable therapy for rescuing neurons from OX-induced firing deficits; 4) take the first step forward in understanding the pathogenesis of OX-induced hypo-excitability by relating its development and underlying biophysics to changes in gene expression of sensory and MNs.

抽象的 化疗通常伴有神经性感觉障碍，可能会限制或终止治疗， 造成长期残疾。目前的研究支持轴突变性和过度兴奋是潜在的 机制。然而，我们最近的研究揭示了一种额外的、绝对新颖的机制， 可能解释化疗相关神经病变中患者功能的丧失。我们在体内获得 电生理测量显示感觉和神经元信号传导功能受损 接受临床相关奥沙利铂 (OX) 治疗方案几周后大鼠运动神经元的变化 化疗。兴奋性低下始终表现为明显无法维持放电 对固定水平刺激的反应。这种缺陷的特殊性使瞬态放电不受影响， 表明 OX 治疗可能会损害感觉和运动中的钠持续内向电流 (NaPIC) 神经元。我们实验室最近发表的研究结果表明，药理阻断促进了这一概念。 NaPIC 模拟 OX 对持续放电的影响。虽然我们的研究结果隔离了化疗的慢性影响 关于神经元的兴奋性，没有化疗就没有癌症。癌症和 OX 疗法可能有效 协同作用于常见的信号通路（例如氧化和炎症）以产生神经元低血压 兴奋性。癌症和 OX 疗法之间相互作用的可能性让我们兴奋不已 初步报告发现大鼠的感觉和运动神经元低兴奋性显着增强 患有结直肠癌。在这里，我们对我们的工作假设进行了深入的测试，即长期使用 OX 治疗 通过减少癌症大鼠模型中的 NaPIC 来损害静态神经元信号传导。我们将测量射击 通过 OX 治疗的癌症大鼠的体内电生理学研究来观察感觉和运动神经元的行为， 为了实现以下四个具体目标：1）检验与癌症相关的相互作用的假设 这些过程会加剧化疗引起的感觉和运动神经元的低兴奋性； 2）测试 假设运动神经元重复放电的慢性缺陷是由于 OX 诱导的 持续的内向电流； 3）开发使大鼠感觉和运动神经元放电正常化的疗法 用 OX 治疗癌症； 4) 确定与 OX 诱导的低兴奋性发展相关的因素 结直肠癌大鼠模型。成功完成这些研究将：1）确定第一个 CIPN 领域的时间，OX 疗法引起神经元兴奋性慢性缺陷的程度， 结直肠癌及其组合； 2）确定中枢神经系统放电缺陷的生物物理机制 OX处理后的神经元； 3）在临床前开发一种可行的疗法，以拯救 OX 诱导的神经元 发射不足； 4）在理解 OX 引起的低兴奋性发病机制方面迈出了第一步 通过将其发展和基础生物物理学与感觉和 MN 基因表达的变化联系起来。