The Role of Astrocyte Elevated Gene-1 (AEG-1), A Novel Multifunctional Protein, In Chemotherapy-Induced Peripheral Neuropathy

星形胶质细胞升高基因 1 (AEG-1)（一种新型多功能蛋白）在化疗引起的周围神经病变中的作用

• 批准号: 10679708
• 负责人: Bryan D Mckiver
• 金额: $ 4.17万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2025-09-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679708
• 关键词: Acetone; Affect; Afferent Neurons; Animal Model; Animals; Astrocytes; Attenuated; Behavior; Behavioral; Biological Assay; Cancer Patient; Categories; Cells; Chemotherapy-induced peripheral neuropathy; Clinical Research; Cytokine Signaling; Data; Development; Dose Limiting; Electrophysiology (science); FDA approved; Female; Genes; Genetic; High Prevalence; Hypersensitivity; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Literature; Macrophage; Macrophage Activation; Maintenance; Measures; Mechanics; Mediating; Mentors; Messenger RNA; Microglia; Molecular; Morphology; Motor Activity; Mus; Myeloid Cell Activation; Myeloid Cells; NF-kappa B; Nerve Fibers; Neural Conduction; Neurons; Neuropathy; Nociception; Oncogenes; Paclitaxel; Pathology; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phosphorylation; Platinum; Play; Pre-Clinical Model; Prevalence; Prevention; Proteins; Quantitative Reverse Transcriptase PCR; Reporting; Role; Running; Signal Pathway; Signal Transduction; Spinal Ganglia; Study models; TNF gene; Testing; Therapeutic; Tissues; Treatment Protocols; Western Blotting; Wild Type Mouse; behavioral response; chemotherapeutic agent; chemotherapy; cytokine; cytotoxic; density; efficacious intervention; falls; mRNA Expression; male; neuroinflammation; neurotoxic; new therapeutic target; nociceptive response; novel; novel therapeutic intervention; pain behavior; prevent; prophylactic; recruit; response; side effect; taxane; transcription factor

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent dose-limiting side effect of chemotherapy treatment and will often result in the discontinuation of a treatment regimen for cancer patients. Taxanes, such as paclitaxel (PAC), are a class of chemotherapeutics that fall into this “high prevalence” category of drugs. There are currently no FDA approved prophylactic or treatment regimens designated to ameliorate CIPN. Peripheral inflammation is a common neurotoxic mechanism among many of the chemotherapeutic agents with a high prevalence of CIPN development in patients. PAC is known to activate peripheral macrophages, leading to a cytotoxic inflammatory response that contributes to the development and maintenance of peripheral neuropathy. Astrocyte Elevated Gene 1 (AEG-1) is a multifunctional protein that operates in a wide variety of intracellular signaling pathways. It has been shown to regulate macrophage activation and mediate cellular inflammation through direct interaction with Nuclear Factor kappa B (NFκB), a key transcription factor protein which regulates the expression of multiple proinflammatory cytokines (PIC). Our preliminary studies demonstrate that nociceptive behaviors and increase in PIC in the dorsal root ganglia (DRG) of mice treated with PAC were significantly reduced in AEG-1 global knockout (KO) mice compared to AEG-1 WT mice, without affecting motor activity and coordination of the animals. We also present data that shows PAC administration increases AEG-1 (MTDH) expression in the DRGs of WT male mice and peripheral macrophages collected from C57BL/6J mice. These findings identify a key role of AEG-1 in regulating nociceptive responses and a potential target for ameliorating CIPN. We hypothesize that AEG-1 mediates PAC-induced neuroinflammation, via macrophage activation leading to the development of CIPN. We will test our hypothesis in Aim 1 by analyzing pain behaviors and various aspects of neuropathy in paclitaxel-induced CIPN in AEG-1 KO and WT mice. We will also assess mRNA expression levels of PIC and protein levels of phosphorylated NFκB in the DRGs collected from PAC treated mice to determine how global AEG-1 deletion impacts PAC-induced neuroinflammation in an NFκB-dependent manner. Aim 2 will investigate the role of macrophage cell AEG-1 expression in PAC-induced neuropathy and neuroinflammation by using myeloid cell- specific conditional AEG-1 KO mouse. Completion of these behavioral and molecular studies will identify AEG-1 expression, particularly in macrophages, as a key driver of neuropathy paving the way for novel therapeutic targets for the treatment or prevention of CIPN.

抽象的 化疗引起的周围神经病变（CIPN）是化疗的一个突出的剂量限制副作用 治疗，通常会导致癌症患者治疗方案的终止。紫杉烷类，例如 紫杉醇 (PAC) 等化疗药物属于这种“高流行”药物类别。 目前尚无 FDA 批准的指定用于改善 CIPN 的预防或治疗方案。 周围炎症是许多化疗药物中常见的神经毒性机制 患者中 CIPN 发生率很高。 PAC 已知可激活外周巨噬细胞， 导致细胞毒性炎症反应，有助于发展和维持 周围神经病变。星形胶质细胞升高基因 1 (AEG-1) 是一种多功能蛋白，其作用范围广泛 多种细胞内信号通路。它已被证明可以调节巨噬细胞的激活并介导 通过与关键转录因子核因子 kappa B (NFκB) 直接相互作用产生细胞炎症 调节多种促炎细胞因子（PIC）表达的蛋白质。我们的初步研究 证明接受治疗的小鼠的伤害感受行为和背根神经节 (DRG) 中 PIC 的增加 与 AEG-1 WT 小鼠相比，AEG-1 全基因敲除 (KO) 小鼠中 PAC 显着减少， 不影响动物的运动活动和协调性。我们还提供了显示 PAC 给药增加 WT 雄性小鼠 DRG 和外周血中 AEG-1 (MTDH) 的表达 从 C57BL/6J 小鼠收集的巨噬细胞。这些发现确定了 AEG-1 在调节中的关键作用 伤害性反应和改善 CIPN 的潜在目标。我们假设 AEG-1 介导 PAC 通过巨噬细胞激活诱导神经炎症，导致 CI​​PN 的发生。我们将测试 我们在目标 1 中的假设是通过分析紫杉醇引起的疼痛行为和神经病变的各个方面来实现的 AEG-1 KO 和 WT 小鼠中的 CIPN。我们还将评估 PIC 的 mRNA 表达水平和 从 PAC 治疗小鼠收集的 DRG 中磷酸化 NFκB，以确定全局 AEG-1 缺失如何 以 NFκB 依赖性方式影响 PAC 诱导的神经炎症。目标 2 将调查的作用 使用骨髓细胞观察 PAC 诱导的神经病变和神经炎症中巨噬细胞 AEG-1 的表达 特定条件AEG-1 KO小鼠。完成这些行为和分子研究将确定 AEG-1 表达，特别是在巨噬细胞中，作为神经病变的关键驱动因素，为新型 治疗或预防 CIPN 的治疗靶点。