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

主要研究者：印章，Sudipta提案编号：1261956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，包括40万美国人。MS通常导致严重残疾，包括无法行走、视力受损或在某些情况下失明和认知功能障碍。虽然免疫调节疗法变得可用，但部分有效，因此，仍然需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，其可以在小鼠中使用髓鞘蛋白如MOG（髓鞘少突胶质细胞糖蛋白）或PLP（蛋白脂质蛋白）诱导。最近，基于纳米技术的方法在各种治疗中显示出了很大的希望。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，并作为有效的再生自由基清除剂。由于炎症在MS病理学基础的轴突损失和脱髓鞘事件中起关键作用，并导致MS患者的残疾，我们检查了NCe对巨噬细胞和T细胞中ROS和炎症的影响，发现NCe治疗淬灭ROS产生，抑制iNOS和COX 2（炎症介质）这项研究将是第一项显示纳米颗粒逆转EAE残疾的治疗潜力的研究，假设/目的：具有抗氧化和抗炎性质的工程化混合价氧化铈纳米颗粒将通过调节适应性免疫应答来抑制MS动物模型中的疾病，并且可以在CNS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的工程化及其生物相容性的全面表征，2）在模拟MS的慢性和复发缓解形式的小鼠模型中检查NCe对适应性免疫应答和恢复残疾的潜力。智力优点：如果成功，该研究将为将该疗法引入MS临床竞技场提供基础和理论依据。使用这种基于纳米技术的疗法的主要优点是：1）：NCe具有再生自由基清除作用和优异的抗氧化性能。2）：NCe在体外和体内小鼠模型中作为抗炎分子。3）：NCe处理保护神经元免受氧化应激并延长其在培养物中的寿命。4）：在小鼠模型中施用NCe是安全的，并且即使使用显著更高的剂量也没有显示出毒性。5）：更重要的是，由于NCe的再生特性，其将限制体内治疗研究期间的重复剂量。EAGER项目的重点是开发纳米稀土颗粒背后的科学，以及其通过中和CNS炎症诱导的氧化应激来恢复MS动物模型残疾的机制。更广泛的影响：这项研究有可能将纳米技术介导的药理学治疗提高到一个新的水平，如果成功的话;它可以为MS提供有效的治疗方法。这一发现不仅限于这些疾病，而且对其他神经退行性疾病具有广泛的影响，这些疾病涉及氧化应激和炎症。在这个概念项目中，我们提出探索NCe在MS动物模型中恢复瘫痪的可能保护作用，这可能对全球数百万接受MS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.