EAGER: Unraveling the mechanism and the role of anti- inflammatory nanoparticles in multiple sclerosis model

PI：Seal，SudiptaProposal编号：1261956多发性硬化症(MS)是一种致残性神经疾病，影响全球250万患者，其中包括40万美国人。多发性硬化症通常会导致严重的残疾，包括无法行走、视力受损，在某些情况下还会失明和认知功能障碍。虽然免疫调节疗法已经出现，但部分有效，因此，仍有必要开发更有效的治疗策略来对抗这种致残性疾病。实验性自身免疫性脑炎(EAE)是一种公认的MS动物模型，可用髓鞘蛋白MOG(髓鞘少突胶质细胞糖蛋白)或PLP(蛋白脂蛋白)诱导小鼠。最近，基于纳米技术的阿帕奇在各种疗法中显示出了很大的前景。在各种纳米颗粒中，氧化铈纳米颗粒(Nanoceria；NCE)是非常独特的，具有优异的抗氧化性能，是一种有效的、可再生的自由基清除剂。由于炎症在MS病理基础上的轴突丢失和脱髓鞘事件中起关键作用，并有助于MS患者的残疾，我们检测了NCE对巨噬细胞和T细胞中ROS和炎症的影响，发现NCE治疗可抑制ROS的生成，抑制iNOS和COX2(炎症介质)。本研究将首次研究纳米粒子逆转MS模型EAE的治疗潜力假设/目的：具有抗氧化和抗炎特性的工程混合价氧化铈纳米颗粒将通过调节适应性免疫反应在MS动物模型中抑制疾病，并可能在CNS提供神经保护(抑制轴突丢失和脱髓鞘)，从而逆转残疾/瘫痪。我们提出了以下目标：1)NCE的工程化及其生物相容性的全面表征；2)研究NCE在模拟慢性和复发缓解型MS小鼠模型中的获得性免疫反应和逆转残疾的潜力。优点：本研究如果成功，将为将该疗法引入MS临床领域提供基础和理论基础。使用这种基于纳米技术的疗法的主要优点是：1)：NCE显示出可再生的自由基清除能力和优异的抗氧化性能。2)：NCE在体外和体内小鼠模型中均具有抗炎作用。3)：NCE处理可保护神经元免受氧化应激，并延长其在培养条件下的寿命。4)：在小鼠模型中给予NCE是安全的，即使在显著较高的剂量下也没有毒性。5)：更重要的是，由于NCE的再生特性，它将限制体内治疗研究中的重复给药。意义/变革性概念这项急切的提议集中在开发纳米稀土颗粒背后的科学及其通过中和中枢神经系统炎症引起的氧化应激来逆转多发性硬化症动物模型中的残疾的机制。更广泛的影响：拟议的研究有可能将纳米技术介导的药物治疗提高到一个新的水平，如果成功，它可以为多发性硬化症提供有效的治疗方法。这一发现将不仅限于这些疾病，还将对涉及氧化应激和炎症的其他神经退行性疾病产生广泛影响。在这个概念项目中，我们建议探索NCE在多发性硬化症动物模型中逆转瘫痪的可能保护作用，这将对全球数百万接受多发性硬化症治疗的人产生巨大的社会影响。

PI: Seal, SudiptaProposal Number: 1261956Multiple Sclerosis (MS) is a disabling neurological disorder affecting 2.5 million patients worldwide including 400,000 Americans. MS often results in severe disability including the inability to walk, impaired vision or in some cases blindness and cognitive dysfunction. Although immunomodulatory therapies became available but are partially effective, therefore, there is a continuing need to develop more effective treatment strategies to combat this disabling disease. Experimental autoimmune encephalitis (EAE) is a well accepted an animal model for MS which can be induced in mice using myelin protein like MOG (Myelin Oligodendrocyte Glycoprotein) or PLP (proteolipid protein). Recently nanotechnology based apporacheshave shown a lot of promise in various therapies. Among various nanoparticles, cerium oxide nanoparticles (nanoceria; NCe) are very unique, possess excellent antioxidant properties and act as potent, regenerative free radical scavengers. Since inflammation play key role in axonal loss and demyelinating events underlying MS pathology and contribute to disability in MS patients, we examined the effect of NCe on ROS and inflammation in macrophage and T cells and found that NCe treatment quenches ROS generation, inhibits iNOS and COX2 (inflammatory mediators) This study will be first study to show the therapeutic potential of nanoparticles to revert the disability in EAE, a model of MS. Hypothesis/Objectives: Engineered mixed valence cerium oxide nanoparticles with antioxidant and anti-inflammatory properties will suppress disease in animal models of MS by modulating adaptive immune responses and may provide neuroprotection (inhibiting axonal loss and demyelination) in the CNS, thereby reverting disability/paralysis. We propose the following aims: 1) Engineering of NCe and its full scale characterization for biocompatibility, 2) Examine the potential of NCe on adaptive immune response and reverting disability in mouse models mimicking chronic and relapsing remitting form of MS. Intellectual Merit: This study, if successful, would provide the groundwork and rationale for introducing this therapy to the MS clinical arena. The main advantages of using this nanotechnology based therapy are: 1): NCe exhibits regenerative free radical scavenging and excellent antioxidant properties. 2): NCe acts as anti-inflammatory molecule in in-vitro as well as in-vivo mice model. 3): NCe treatment protects neurons against oxidative stress and prolongs their life span in culture. 4): Administration of NCe in mouse model is safe and shows no toxicity even with significantly higher doses. 5): More importantly, due to the regenerative property of NCe, it will limit the repeated doses during therapeutic studies in vivo. Significance/Transformative Concept This EAGER proposal focuses on the science behind developing nano rare earth particles and its mechanism in reverting disability in animal models of MS by neutralizing oxidative stress induced generated by inflammation in CNS. Broader Impact: The proposed study has potential to take nanotechnology mediated pharmacological treatment to a new level, if successful; it can provide effective therapies for MS. The finding will not be just confined to these diseases but has broad implications to other neurodegenerative diseases, which involve oxidative stress and inflammation. In this concept project we proposed to explore possible protection of NCe in reverting paralysis in animal models of MS which can have a big societal impact on the millions of people worldwide on MS treatment.