Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system

靶向 p38/JNK MAPK 改善顺铂引起的神经系统不良后遗症

基本信息

批准号：
10437925
负责人：
Daniela Annenelie Bota
金额：
$ 61.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437925
关键词：
Adverse effects Affect Aftercare Alzheimer&apos s Disease Antineoplastic Agents Apoptosis Attention Attenuated Axon Behavioral Bioenergetics Blood - brain barrier anatomy Brain Breast Breast Cancer Model C57BL/6 Mouse Cancer Model Cancer Patient Cell Line Chemotherapy-induced peripheral neuropathy Cisplatin Clinical Clinical Trials Cognitive Cognitive deficits DNA Damage Data Dendritic Spines Development Diagnosis Disease Progression Dose Electrophysiology (science)Epithelial ovarian cancer Excitatory Synapse FDA approved Female Fracture Gait Hippocampus (Brain)Impaired cognition Impairment In Vitro Individual Inflammation Intervention Kidney Length MAPK8 gene Malignant Neoplasms Malignant neoplasm of ovary Memory Mitochondria Mitochondrial DNA Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Molecular Morphology Motor Mus N-terminal Nerve Nerve Fibers Nervous system structure Neurologic Neurons Neuropathy Nuclear Numbness Ovarian Oxidative Stress Oxygen Painful Paresthesias Pathway interactions Patients Performance Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacology Phosphotransferases Platinum Compounds Play Preventive treatment Process Protein Kinase Protein Kinase C Quality of life Rattus Reporting Rodent Model Role SP600125 Sensory Signal Pathway Signal Transduction Skin Small Interfering RNA Spinal Ganglia Spinal Injuries Symptoms Testing Time Toxic effect Transgenic Organisms United States Vinca Alkaloids Woman anticancer activity attenuation axon injury base cancer pain cancer therapy chemobrain chemotherapeutic agent chemotherapy cognitive testing density disability druggable target executive function experience falls health disparity improved in vivo information processing inhibitor kinase inhibitor male malignant breast neoplasm men multidisciplinary neuron apoptosis neurotoxic neurotoxicity neurotransmission novel novel strategies novel therapeutics ototoxicity p38 Mitogen Activated Protein Kinase painful neuropathy patient mobility peripheral nerve damage prevent processing speed relating to nervous system side effect small molecule inhibitor stem stem cells taxane translational potential

项目摘要

Chemotherapy-related cognitive impairment (CRCI, chemobrain), chemotherapy-induced peripheral neuropathy (CIPN) and gait changes are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin), taxanes, and vinca alkaloids. Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies. Over 70% of women report experiencing CRCI, CIPN and/or falls during treatment or after completion, impairing their quality of life. These neurotoxic impairments can also compromise treatment with cisplatin, influencing disease progression. Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and CIPN. Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage, and oxidative stress, which induce the activation of the mitogen-activated protein kinases (MAPK), p38MAPK and c-Jun N-terminal kinase (JNK), leading to neuronal apoptosis. Our preliminary data show that in vitro pharmacological inhibition with small molecule inhibitors, i.e., neflamapimod for p38MAPK and SP600125 for JNK, prevents cisplatin-induced reduction in dendritic spine branching and density. Based on these data, we hypothesize that inhibition of the p38MAPK/JNK pathways will prevent cisplatin-induced neuronal apoptosis and damage, leading to attenuation of cognitive impairments, gait changes, and neuropathic pain associated with CRCI and CIPN. In this project, we propose to determine if: (1) cisplatin-induced p38 MAPK/JNK signaling underlies structural and functional neuronal damage, using in vitro pharmacological inhibition and siRNA silencing; (2) neflamapimod and SP600125 prevent cisplatin-induced neuropathy and gait alterations in the ID8 syngeneic epithelial ovarian cancer in C57BL/6 mice and the transgenic breast cancer model C3TAg in FVBN mice; and (3) cisplatin-induced neurotoxicity is attenuated by p38MAPK/JNK inhibition without compromising its anti-cancer activity. Our Approach includes in vitro analysis of 2 separate neuronal cell lines, behavioral analysis using sensory testing for CIPN, testing of cognitive impairment, and novel MouseWalker for gait changes in female mice using the two mouse cancer models. The proposed studies will demonstrate the role of the p38MAPK and JNK in cisplatin induced CRCI/CIPN, and translational potential for novel strategies to treat CRCI and CIPN. Due to health disparities, women suffer more disproportionately from cancer and pain-related treatment than men. Therefore, testing our hypothesis in female mice is expected to significantly advance the understanding and treatment of cisplatin-induced neurotoxic side effects and improve the quality of life for women with cancer. Nevertheless, we expect that these findings may also apply to cisplatin- induced neurotoxicity in males and to other cancers than ovarian and breast cancers.

化学疗法相关的认知障碍（CRCI，Chemobrain），化学疗法诱导的周围神经病（CIPN）和步态变化是用铂剂（例如顺铂），癌症治疗的副作用使人衰弱紫杉虫和芬卡生物碱。顺铂被广泛用作治疗卵巢恶性肿瘤的化学治疗剂。超过70％的妇女报告在治疗期间或完成后经历CRCI，CIPN和/或跌倒，损害他们的生活质量。这些神经毒性障碍也会损害以顺铂的治疗，影响疾病进展。目前，没有FDA批准的临床干预措施用于治疗CRCI和 CIPN。从机械上讲，顺铂诱导的神经元毒性源自核和线粒体DNA损伤，和氧化应激，诱导有丝分裂原激活蛋白激酶（MAPK），p38mapk的激活和C-JUN N末端激酶（JNK），导致神经元细胞凋亡。我们的初步数据表明体外用小分子抑制剂的药理抑制作用，即p38mapk的Neflamapimod和SP600125用于 JNK，可防止顺铂诱导的树突状脊柱分支和密度降低。基于这些数据，我们假设抑制p38mapk/jnk途径将阻止顺铂诱导的神经元细胞凋亡和损害，导致认知障碍，步态变化和神经疗法的衰减与CRCI和CIPN相关的疼痛。在这个项目中，我们建议确定是否：（1）顺铂诱导的p38 MAPK/JNK信号传导是使用体外药理的结构和功能性神经元损伤的基础抑制和siRNA沉默；（2）Neflamapimod和SP600125防止顺铂引起的神经病和步态 C57BL/6小鼠和转基因乳腺癌的ID8同皮上皮卵巢癌的改变 FVBN小鼠中的C3TAG模型；（3）顺铂诱导的神经毒性被p38mapk/jnk抑制减弱不损害其抗癌活性。我们的方法包括对2个单独神经元细胞的体外分析线条，使用感官测试的行为分析，认知障碍的测试和新颖使用两种小鼠癌模型的雌性小鼠步态变化的小鼠行走器。拟议的研究将演示p38mapk和JNK在顺铂诱导的CRCI/CIPN中的作用，以及转化潜力治疗CRCI和CIPN的新型策略。由于健康差异，妇女遭受的遭受的遭受癌症和与疼痛有关的治疗比男性。因此，预计在雌性小鼠中测试我们的假设显着提高顺铂诱导的神经毒性副作用并改善的理解和治疗癌症女性的生活质量。但是，我们希望这些发现也可能适用于顺铂 - 除卵巢和乳腺癌以外，雄性和其他癌症诱导了神经毒性。