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: 10227137
• 负责人: Timothy C Cope
• 金额: $ 30.54万
• 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/10227137
• 关键词: Acute; Adopted; 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; side effect; 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.

摘要 化疗通常伴有神经性感觉障碍，这可能限制或终止治疗， 造成长期残疾。目前的研究支持轴突变性和过度兴奋作为潜在的 机制等然而，我们最近的研究揭示了一个额外的，绝对新颖的机制， 可能导致化疗相关神经病变患者功能丧失。我们在体内获得了 电生理学测量显示来自感觉和感觉神经元信号传导的功能损伤， 接受临床相关奥沙利铂（OX）方案后数周，大鼠运动神经元 化疗低兴奋性一致表示为明显的失败，以维持射击， 对固定刺激水平的反应。这种缺陷的特异性，使瞬时放电不受影响， 提示OX治疗可能损害感觉和运动神经元中的钠持续内向电流（NaPIC）。 神经元我们实验室发表的最新研究结果通过表明， NaPIC模拟OX对持续放电的影响。虽然我们的研究结果将化疗的慢性效应 对神经元兴奋性的影响，没有化疗就没有癌症。癌症和OX疗法可能会 协同作用于共同的信号传导途径（例如氧化和炎症），以产生神经元低- 兴奋性癌症和OX治疗之间相互作用的可能性从我们的研究中获得了兴奋。 初步报告发现，感觉和运动神经元的低兴奋性在大鼠中显着放大 结直肠癌在这里，我们提出了尖锐的测试我们的工作假设，OX治疗慢性 通过减少大鼠癌症模型中的NaPIC来损害静态神经元信号传导。我们将测量射击 感觉和运动神经元的行为通过用OX处理的癌症大鼠的体内电生理学研究， 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， 过程加剧化疗诱导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OX诱导的 持续性内向电流; 3）开发使大鼠感觉和运动神经元放电正常化的治疗方法 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， 一种结直肠癌的大鼠模型。这些研究的成功完成将：1）确定为第一个 CIPN场中的时间，OX治疗引起神经元兴奋性的慢性缺陷的程度， 结直肠癌及其组合; 2）确定CNS放电缺陷的生物物理机制 OX治疗后的神经元; 3）临床前开发一种可行的治疗方法，用于拯救OX诱导的神经元 放电缺陷; 4）在理解OX诱导的低兴奋性的发病机制方面迈出了第一步 通过将其发展和潜在的生物物理学与感觉和MN的基因表达变化联系起来。