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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.

摘要

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.