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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：
10442405
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442405
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 Persons 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 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.

奥沙利铂相关化疗诱导的周围神经病变（CIPN）是一种常见的，潜在的严重和剂量限制性毒性的结直肠癌治疗。CIPN的总发病率估计为在患者中大约有40%以上。CIPN可在化疗后持续数月至数年完成，由于其对生活质量的负面影响，对癌症幸存者造成重大挑战（QOL）。CIPN是一个重要的挑战，因为缺乏可以有效预防或治疗的治疗方法。减轻药物的不良反应。我们已经确定了特定的受体介导的途径，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批准的用于其它疾病的药物条件这项建议强调了一个多学科的研究计划，建立在我们的初步数据，探索CIPN的机制以及FDA批准的药物可以重新用于治疗或预防的条件。在目标1中，我们将研究铂-DNA加合物的影响，啮齿动物暴露于奥沙利铂后释放高迁移率族蛋白1（HMGB 1）。在目标2中，我们将研究受体Toll样受体（TLR 4）是否负责发展或维持跨时间的CIPN最后，在目标3中，我们将对FDA批准的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，这可能会改变奥沙利铂对感觉神经元的不利影响。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Concentrations of HMGB1 and Hsp70 of healthy subjects in upper and lower airway: Literature Review and Meta-analysis.

DOI：
10.7150/ijms.53500
发表时间：
2021
期刊：
International journal of medical sciences
影响因子：
3.6
作者：
Min HJ;Kim KS;Choi GJ;Kang H;White FA
通讯作者：
White FA

The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study.

DOI：
10.1186/s10194-020-01207-1
发表时间：
2020-12-03
期刊：
The journal of headache and pain
影响因子：
0
作者：
Naugle KM;Carey C;Evans E;Saxe J;Overman R;White FA
通讯作者：
White FA

Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.

DOI：
10.1111/epi.17069
发表时间：
2021-12
期刊：
Epilepsia
影响因子：
5.6
作者：
通讯作者：

Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels.

DOI：
10.3390/ijms24010877
发表时间：
2023-01-03
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Ludwig, Nora;Demaree, Isaac S.;Yamada, Chiaki;Nusbaum, Amilia;Nichols, Frank C.;White, Fletcher A.;Movila, Alexandru;Obukhov, Alexander G.
通讯作者：
Obukhov, Alexander G.

Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation.