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

基本信息

批准号：
10460998
负责人：
Timothy C Cope
金额：
$ 29.89万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460998
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

项目摘要

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.

抽象的化学疗法通常伴随着可以限制或终止治疗的神经性感觉障碍导致长期残疾。当前的研究支持轴突变性和过度兴奋性机制。但是，我们最近的研究揭示了一种其他绝对新颖的机制潜在说明与化学疗法相关的神经病中患者功能丧失的潜力。我们在体内获得了电生理测量表明，从感觉和接受奥沙利铂（OX）的临床相关方案（OX）几周后的大鼠运动神经元化学疗法。始终表达了低兴趣性的性能对固定刺激水平的反应。该缺陷的特异性，使瞬态发射不受影响，表明ox处理可能会损害感觉和运动中的钠持续的内向电流（NAPIC）神经元。在我们的实验室中发表的最新发现通过表明该概念的药理阻滞纳入模仿牛对持续发射的影响。而我们的发现分离了化学疗法的慢性作用关于神经元兴奋性，没有癌症就没有化学疗法。癌症和牛治疗可能会起作用在共同信号通路（例如氧化和炎症性）上协同作用，以产生神经元低 - 兴奋性。癌症与OX治疗之间相互作用的可能性从我们的大鼠发现感官和运动神经元低兴趣性的初步报道显着放大结直肠癌。在这里，我们提出了我们的工作假设的敏锐检验通过减少大鼠癌模型中的纳入纳性纳性，损害静态神经元信号。我们将衡量射击通过体内电生理研究对用OX治疗的癌症大鼠的体内电生理研究的行为，为了实现以下四个特定目标：1）检验与癌症相互作用相互作用的假设过程加剧了化学疗法诱导的感觉神经元中的缺点； 2）测试假设运动神经元重复发射的慢性缺陷是由于牛引起的下降而引起的持续的内流电流； 3）开发将大鼠感觉和运动神经元发射归一化的治疗用牛治疗癌症； 4）确定与OX在大鼠结直肠癌的模型。这些研究的成功完成将：1）确定第一个在CIPN领域，慢性缺陷在神经元兴奋性中的程度是由OX治疗引起的结直肠癌及其结合； 2）确定CNS发射缺陷的生物物理机制牛治疗后神经元； 3）在链式前开发一种可行的疗法，用于从OX诱导的解雇赤字； 4）向前迈出的第一步，了解牛诱导的性不足性的发病机理通过将其发育和潜在的生物物理学与感觉和MN的基因表达的变化联系起来。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat.

DOI：
10.1016/j.neuro.2021.08.002
发表时间：
2021-09
期刊：
NEUROTOXICOLOGY
影响因子：
3.4
作者：
Housley, Stephen N.;Rotterman, Travis M.;Nardelli, Paul;Carrasco, Dario I.;Noel, Richard K.;O'Farrell, Laura;Cope, Timothy C.
通讯作者：
Cope, Timothy C.

Neural circuit mechanisms of sensorimotor disability in cancer treatment.

DOI：
10.1073/pnas.2100428118
发表时间：
2021-12-21
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Housley SN;Nardelli P;Rotterman TM;Cope TC
通讯作者：
Cope TC

Chronic defects in intraspinal mechanisms of spike encoding by spinal motoneurons following chemotherapy.

DOI：
10.1016/j.expneurol.2020.113354
发表时间：
2020-09
期刊：
Experimental neurology
影响因子：
5.3
作者：
Housley SN;Nardelli P;Powers RK;Rich MM;Cope TC
通讯作者：
Cope TC

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics.

DOI：
10.7554/elife.55177
发表时间：
2020-12-28
期刊：
eLife
影响因子：
7.7
作者：
Blum KP;Campbell KS;Horslen BC;Nardelli P;Housley SN;Cope TC;Ting LH
通讯作者：
Ting LH

Imbalanced Subthreshold Currents Following Sepsis and Chemotherapy: A Shared Mechanism Offering a New Therapeutic Target?

DOI：
10.1177/1073858420981866
发表时间：
2022-04
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
0
作者：
Rich MM;Housley SN;Nardelli P;Powers RK;Cope TC
通讯作者：
Cope TC