The role of the astrocyte immunoproteasome during chronic CNS autoimmunity

项目摘要/摘要 本项目的目的是确定慢性进行性脑缺血患者神经保护的一种新途径。 免疫介导型疾病多发性硬化症(MS)的各个阶段。慢性进展性多发性硬化症 神经退行性，而不是炎症性的；因此，批准的治疗方法，所有这些都是令人惊讶的 具有免疫调节作用，对进展性多发性硬化症患者疗效有限。因此，最重要的是 多发性硬化症研究的必要性是理解潜在的进展机制，以便识别新的 进行性多发性硬化症的治疗靶点 我们先前的研究表明，免疫细胞因子作用于区域性异种星形胶质细胞以产生 在成人中枢神经系统(CNS)损伤后的保护和修复过程中的有益影响。自.以来 星形胶质细胞在MS病变中含量丰富，在中枢神经系统功能和动态平衡中起关键调节作用。 炎症，我们假设星形胶质细胞在免疫调节过程中起着关键的调节作用 慢性神经炎。针对这一假说，我们发现了一种新的干扰素γ调节途径。 进行性多发性硬化症患者组织中的慢性白质病变星形胶质细胞活跃。我们继续前行 为了发现干扰素γ优先介导原代星形胶质细胞免疫蛋白酶体(IP)的上调， 这会减少破坏性的氧化应激，并防止慢性疾病恶化 实验性自身免疫性脑脊髓炎(EAE)的MS小鼠活体模型。以强劲的前期工作为指导 数据，我们建议追求三个特定的目标来阐明干扰素γ如何通过星形胶质细胞介导中枢神经系统保护。 慢性神经炎期间的IP： 1)测定干扰素γ-IP轴在MS和EAE过程中星形胶质细胞的表达动态。 2)确定干扰素γ介导的存活和活性氧(ROS)机制 星形胶质细胞的清除。 3)研究星形细胞IP在调节神经退行性变中的作用。 总而言之，我们提出的研究战略将通过剖析以前的 未知的动力学和机制潜在的未知途径，是活跃在星形胶质细胞 神经炎症，它将揭示免疫细胞因子和IP在 长期的慢性多发性硬化症，这些研究可能揭示进展性多发性硬化症患者的新治疗策略和 有可能被推断为其他已知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.