The role of cell-specific TLR-4 signaling in oxaliplatin-induced peripheral neuropathy

细胞特异性 TLR-4 信号在奥沙利铂诱导的周围神经病变中的作用

• 批准号: 10194622
• 负责人: FLETCHER A WHITE
• 金额: $ 43.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194622
• 关键词: AVIL gene; Action Potentials; Acute; Address; Adjuvant Therapy; Adverse drug effect; Afferent Neurons; Agonist; Alleles; Animals; Antiepileptic Agents; Attenuated; Behavior; Behavior Therapy; Behavioral; Behavioral Assay; Biological Assay; Calcium; Cancer Patient; Cancer Survivor; Carboplatin; Cells; Characteristics; Chemotherapy-induced peripheral neuropathy; Chronic; Cisplatin; Clinical; Clinical Treatment; Clinical Trials; Colorectal Cancer; Cytosol; DNA; DNA Adducts; Data; Development; Disease; Dose; Dose-Limiting; Drug usage; Dysesthesias; Enterobacteria phage P1 Cre recombinase; Enzymes; Excision; Exposure to; FDA approved; Future; Gender; Generations; Genes; Goals; HMGB1 Protein; Hypersensitivity; Image; Immune; In Vitro; Incidence; Inflammation Mediators; Interdisciplinary Study; Interleukin-1 Receptors; Interruption; Ion Channel; Ions; Lead; Maintenance; Measures; Mediating; Methodology; Methods; Motor; Mus; Names; National Cancer Institute; Nerve Fibers; Neurites; Neurons; Nociception; Nuclear Protein; Nuclear Translocation; Numbness; Pain; Paresthesia; Pathway interactions; Patients; Performance; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Platinum; Platinum adduct; Poly(ADP-ribose) Polymerases; Population; Pre-Clinical Model; Prevention; Property; Publications; Quality of life; Receptor Signaling; Reflex action; Reporting; Rodent; Role; Signal Transduction; Sodium Channel; Spinal Ganglia; Symptoms; TLR1 gene; TLR4 gene; Tamoxifen; Testing; Therapeutic; Time; Toll-like receptors; Toxic effect; Translations; Vinca Alkaloids; Work; allodynia; base; cancer cell; chemotherapy; colon cancer patients; colorectal cancer treatment; crosslink; cytokine; drug development; efficacy evaluation; ganglion cell; in vivo; inhibitor/antagonist; innovation; nerve supply; neurotoxic; new therapeutic target; novel therapeutics; oxaliplatin; pain behavior; peripheral pain; phenotypic biomarker; prevent; promoter; receptor; relating to nervous system; small molecule; small molecule inhibitor; taxane; therapeutic target; tumor; voltage

Oxaliplatin-associated Chemotherapy-induced Peripheral Neuropathy (CIPN) is a frequent, potentially severe and dose-limiting toxicity of colorectal cancer treatment. The overall incidence of CIPN is estimated to be approximately upwards of 40% in patients. CIPN can persist for months to years beyond chemotherapy completion, causing significant challenges for cancer survivors due to its negative influence on quality of life (QOL). CIPN represents an important challenge because of the lack of treatment that can effectively prevent or mitigate this adverse drug effect. We have identified specific receptor-mediated pathways which contribute to increases in ion current as a potential therapeutic target for the treatment or prevention of CIPN. Noteworthy, several ion channel modulators central to CIPN treatment are FDA-approved drugs used for other disease conditions. This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore both the mechanism of CIPN and the degree to which FDA-approved drugs can be repurposed for the treatment or prevention of the condition. In Aim 1, we will examine the influence of platinum-DNA adducts and release of high mobility group box-1 (HMGB1) in rodents following exposure to oxaliplatin. In Aim 2, we will investigate whether the receptor Toll-like receptor (TLR4) is responsible for the development or maintenance of CIPN across time. Finally, in Aim 3, we will conduct a proof of concept assessment of the efficacy of FDA-approved antiepileptic drugs on both neuronal ion currents and CIPN behavioral characteristics. These proposed studies will provide new therapeutic targets which will likely alter the detrimental effects of oxaliplatin on sensory neurons.

奥沙利铂相关化疗所致周围神经病(CIPN)是一种常见的、潜在的 结直肠癌治疗的严重毒性和剂量限制性毒性。据估计，CIPN的总发病率为 患者中约有40%以上。CIPN可在化疗后持续数月至数年 完成，由于对生活质量的负面影响，给癌症幸存者带来了巨大的挑战 (QOL)。CIPN是一个重要的挑战，因为缺乏可以有效预防或 减轻这种药物的不良影响。我们已经确定了特定的受体介导的通路，这些通路有助于 增加离子电流作为治疗或预防CIPN的潜在治疗靶点。值得注意的是， 几种对CIPN治疗至关重要的离子通道调节剂是FDA批准的用于其他疾病的药物 条件。这项建议强调了一个多学科研究计划，该计划建立在我们的初步数据基础上 探索CIPN的机制以及FDA批准的药物可以在多大程度上重新用于 疾病的治疗或预防。在目标1中，我们将研究铂-DNA加合物和 奥沙利铂对啮齿动物体内高迁移率族蛋白1(HMGB1)的释放在目标2中，我们将 探讨受体Toll样受体(TLR4)是否参与了Toll样受体的形成或维持 跨越时间的CIPN。最后，在目标3中，我们将对FDA批准的药物的有效性进行概念验证评估 抗癫痫药物对神经元离子电流和CIPN行为特征的影响。这些拟议的研究将提供新的治疗靶点，可能会改变奥沙利铂对感觉神经元的有害影响。