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

多发性硬化症（MS）是一种致残性神经系统疾病，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，在某些情况下还会导致失明和认知功能障碍。虽然免疫调节疗法已经可用，但部分有效，因此，仍然需要制定更有效的治疗战略来防治这种致残疾病。实验性自身免疫性脑炎（EAE）是一种公认的多发性硬化症动物模型，可以用髓鞘蛋白如髓鞘少突胶质细胞糖蛋白（MOG）或蛋白脂质蛋白（PLP）在小鼠中诱导。最近，基于纳米技术的方法在各种治疗中显示出很大的希望。在各种纳米粒子中，氧化铈纳米粒子（nanoceria; NCe）是非常独特的，具有优异的抗氧化性能，是一种有效的再生自由基清除剂。由于炎症在MS病理背后的轴突损失和脱髓鞘事件中起着关键作用，并导致MS患者残疾，因此我们研究了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的产生，抑制iNOS和COX2（炎症介质）。本研究将首次证明纳米颗粒在恢复MS模型EAE中残疾的治疗潜力。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来抑制MS动物模型中的疾病，并可能在中枢神经系统中提供神经保护（抑制轴突损失和脱髓鞘），从而恢复残疾/瘫痪。我们提出以下目标：1)NCe工程及其生物相容性的全面表征；2)在模拟慢性和复发缓解型多发性硬化症的小鼠模型中，研究NCe在适应性免疫反应和恢复残疾方面的潜力。智力优势：如果这项研究成功，将为将这种疗法引入多发性硬化症临床领域提供基础和理论依据。使用这种纳米技术治疗的主要优点是：1):NCe具有再生自由基清除和优异的抗氧化性能。2): NCe在体外和体内小鼠模型中均有抗炎分子作用。3): NCe处理可保护神经元抗氧化应激，延长其在培养中的寿命。4): NCe给药小鼠模型是安全的，即使显著增加剂量也无毒性。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剂量。本EAGER提案重点关注纳米稀土颗粒开发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而恢复MS动物模型残疾的机制。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升到一个新的水平，如果成功的话；这一发现不仅局限于这些疾病，而且对其他涉及氧化应激和炎症的神经退行性疾病也有广泛的意义。在这个概念项目中，我们提出探索NCe在多发性硬化症动物模型中恢复瘫痪的可能保护作用，这可能对全世界数百万接受多发性硬化症治疗的人产生重大的社会影响。

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.