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.

摘要 化疗引起的周围神经病变（CIPN）是化疗的一个显著的剂量限制性副作用 这将导致癌症患者的治疗方案的中断。紫杉烷类，如 如紫杉醇（PAC），是属于这种“高流行率”药物类别的一类化学治疗剂。 目前没有FDA批准的指定用于改善CIPN的预防或治疗方案。 外周炎症反应是多种化疗药物常见的神经毒性机制 在患者中CIPN的发生率很高。已知PAC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，在广泛的细胞内发挥作用。 多种细胞内信号通路。它已被证明可以调节巨噬细胞激活并介导 通过与核因子κ B（NFκB）（一种关键转录因子）直接相互作用引起细胞炎症 调节多种促炎细胞因子（PIC）表达的蛋白质。我们的初步研究 证明了治疗的小鼠的伤害性行为和背根神经节（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的表达显著降低， 而不影响动物的运动活动和协调性。我们还提供了数据，显示PAC 给药增加WT雄性小鼠和外周血中DRG中AEG-1（MTDH）的表达。 从C57 BL/6 J小鼠收集的巨噬细胞。这些发现确定了AEG-1在调节 伤害性反应和改善CIPN的潜在靶点。我们假设AEG-1介导了 PAC诱导的神经炎症，通过巨噬细胞活化导致CIPN的发展。我们将测试 我们在目标1中的假设，通过分析紫杉醇诱导的疼痛行为和神经病变的各个方面， 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处理的小鼠收集的DRG中的磷酸化NFκB，以确定整体AEG-1缺失如何 以NFκ B依赖的方式影响PAC诱导的神经炎症。目标2将研究 用骨髓细胞检测巨噬细胞AEG-1在PAC诱导的神经病变和神经炎症中的表达 特异性条件性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，为新的神经病变铺平了道路。 用于治疗或预防CIPN的治疗靶标。