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

基本信息

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
项目类别：
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

项目摘要

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.

奥沙利铂相关化疗引起的周围神经病变 (CIPN) 是一种常见的、潜在的结直肠癌治疗的严重和剂量限制性毒性。 CIPN 的总体发生率估计为患者中大约有 40% 以上。 CIPN 可以在化疗后持续数月至数年由于其对生活质量的负面影响，给癌症幸存者带来了重大挑战（生活质量）。 CIPN 是一个重要的挑战，因为缺乏可以有效预防或预防的治疗方法。减轻这种药物的不良作用。我们已经确定了特定的受体介导的途径，这些途径有助于离子电流的增加作为治疗或预防 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 批准用于其他疾病的药物状况。该提案强调了一项多学科研究计划，该计划以我们的初步数据为基础探索 CIPN 的机制以及 FDA 批准的药物可以重新用于新用途的程度治疗或预防该病症。在目标 1 中，我们将研究铂-DNA 加合物的影响和啮齿类动物接触奥沙利铂后会释放高迁移率族蛋白盒-1 (HMGB1)。在目标 2 中，我们将研究受体 Toll 样受体 (TLR4) 是否负责发育或维持 CIPN 跨越时间。最后，在目标 3 中，我们将对 FDA 批准的药物的功效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。