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

摘要 化疗所致周围神经病(CIPN)是化疗的一个突出的剂量限制性副作用 而且往往会导致癌症患者的治疗方案中断。紫杉烷等 如紫杉醇(PAC)，是属于这种“高流行”药物类别的一类化疗药物。 目前还没有FDA批准的预防或治疗方案指定用于改善CIPN。 在许多化疗药物中，外周炎症是常见的神经毒性机制。 具有高患病率的CIPN患者。已知PAC可以激活外周巨噬细胞， 导致细胞毒性炎症反应，有助于发展和维持 周围神经病。星形胶质细胞升高基因1(AEG-1)是一种多功能蛋白，在 细胞内信号通路的多样性。它已被证明调节巨噬细胞的激活和调节 核转录因子κB与核因子kappaB的直接相互作用引起的细胞炎症 调节多种促炎细胞因子(PIC)表达的蛋白质。我们的初步研究 给药小鼠背根神经节伤害性行为和PIC的增加 与AEG-1WT小鼠相比，AEG-1全局基因敲除(KO)小鼠的PAC显著减少， 而不影响动物的运动活动和协调性。我们还提供了显示PAC的数据 给药增加WT雄性小鼠及外周背根神经节AEG-1(MTDH)的表达 巨噬细胞取自C57BL/6J小鼠。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通过 PAC通过激活巨噬细胞诱导神经炎症，导致CIPN的发生。我们将测试 通过分析紫杉醇诱导的疼痛行为和神经病变的不同方面，我们在目标1中的假设 AEG-1、KO和WT小鼠的CIPN。我们还将评估PIC的mRNA表达水平和蛋白水平 从PAC处理的小鼠收集的DRG中磷酸化的NFκB以确定全局AEG-1缺失如何 以依赖于核因子κB的方式影响PAC诱导的神经炎症。目标2将调查 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。这些行为和分子研究的完成将确定 AEG-1的表达，特别是在巨噬细胞中的表达，作为神经病变的关键驱动因素，为新的 治疗或预防CIPN的治疗靶点。

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.