The role of the astrocyte immunoproteasome during chronic CNS autoimmunity

项目总结/摘要 本项目的目的是确定一种新的神经保护途径，在慢性进行性脑梗死中， 免疫介导的疾病多发性硬化症（MS）的阶段。慢性进行性MS主要是 神经退行性疾病，而不是炎症;因此，这并不奇怪，批准的治疗，所有这些， 是免疫调节性的，在治疗进行性MS患者中具有有限的功效。因此， MS研究的必要性是了解进展的机制，以确定新的 治疗进展性MS的治疗靶点。 我们以前的研究表明，免疫细胞因子作用于区域异质性星形胶质细胞， 在损伤后成人中枢神经系统（CNS）的保护和修复过程中发挥有益作用。以来 星形胶质细胞在MS病变中是丰富的，并且在MS病变期间在CNS功能和体内平衡中具有关键的调节作用。 我们假设星形胶质细胞在炎症过程中作为免疫介导过程的关键调节因子， 慢性神经炎症针对这一假设，我们确定了一种新的干扰素（IFN）γ调节途径， 在进行性、死后MS患者组织内的慢性白质病变星形胶质细胞中具有活性。我们去 为了发现IFNγ优先介导原代星形胶质细胞中免疫蛋白酶体（iP）的上调， 这导致减少破坏性的氧化应激和保护免受恶化的慢性疾病， MS，实验性自身免疫性脑脊髓炎（EAE）体内鼠模型。以强有力的初步指导 数据，我们建议追求三个特定的目的，以阐明IFNγ如何介导中枢神经系统保护通过星形胶质细胞 慢性神经炎症期间iP： 1)确定MS和EAE期间星形胶质细胞中IFNγ-iP轴的表达动力学。 2)确定IFNγ介导的存活和活性氧（ROS）的机制 清除星形胶质细胞。 3)检查星形胶质细胞iP在调节神经变性中的作用。 总的来说，我们提出的研究战略将广泛影响该领域的解剖以前， 一个未知的动力学和机制，潜在的一个未描述的途径，是活跃在星形胶质细胞， 它将揭示免疫细胞因子和iP在神经炎症中的范式转移保护作用， 长期来看，这些研究可能揭示进展性MS患者的新治疗策略， 有可能外推到其他已知iP功能障碍的神经退行性疾病。

PROJECT SUMMARY/ABSTRACT The purpose of this project is to identify a novel pathway of neuroprotection in the chronic progressive phases of the immune-mediated disease multiple sclerosis (MS). Chronic progressive MS is largely neurodegenerative as opposed to inflammatory; thus, it is not surprising that approved treatments, all of which are immunomodulatory, have limited efficacy in treating progressive MS patients. Therefore, a paramount necessity in MS research is to understand the mechanisms underlying progression in order to identify novel therapeutic targets for the treatment of progressive MS. Our previous studies revealed that immune cytokines act on regionally heterogenous astrocytes to yield beneficial effects during protection and repair of the adult central nervous system (CNS) following injury. Since astrocytes are abundant in MS lesions and have a critical regulatory role in CNS function and homeostasis during inflammation, we hypothesized that astrocytes act as a pivotal regulator of immune-mediated processes during chronic neuroinflammation. Towards this hypothesis, we identified a novel, interferon (IFN)γ-regulated pathway active in chronic white-matter lesion astrocytes within progressive, postmortem MS patient tissue. We went on to discover that IFNγ preferentially mediates upregulation of the immunoproteasome (iP) in primary astrocytes, which leads to a reduction in damaging oxidative stress and protection from exacerbated chronic disease in an in vivo murine model of MS, experimental autoimmune encephalomyelitis (EAE). Guided by strong preliminary data, we propose to pursue three Specific Aims to elucidate how IFNγ mediates CNS protection via the astrocyte iP during chronic neuroinflammation: 1) Determine the expression kinetics of the IFNγ-iP axis in astrocytes during MS and EAE. 2) Identify the mechanisms responsible for IFNγ-mediated survival and reactive oxygen species (ROS) clearance in astrocytes. 3) Examine the role of astrocytic iP in modulating neurodegeneration. Collectively, our proposed research strategy will broadly impact the field by dissecting previously unknown kinetics and mechanisms underlying an undescribed pathway that is active in astrocytes during neuroinflammation and it will reveal a paradigm-shifting protective role for immune cytokines and the iP during chronic MS. Long-term, these studies may reveal novel therapeutic strategies for progressive MS patients and have the potential to be extrapolated to other neurodegenerative diseases with known iP dysfunction.