Cytokines in Glial Cells and EAE Brain

描述(申请人提供)：多发性硬化症(MS)是一种炎症性脱髓鞘疾病，导致少突胶质细胞、髓鞘和轴突丢失，并形成神经退行性病变。目前针对免疫调节机制开发的药物疗效有限，因为尽管进行了治疗，但中枢神经系统疾病的进展仍在继续。包括我们在内的不同实验室的研究已经提供了线粒体和过氧化物体功能异常是EAE(实验性自身免疫性脑脊髓炎)和MS中枢神经系统疾病病理的原因之一的证据，但对于导致这些疾病的机制几乎没有(如果有的话)。本提案旨在了解线粒体和过氧化物体功能障碍的机制，并确定针对这些病理机制的药物在EAE中的神经保护和神经修复的疗效。最近，我们描述了RhoA-Rock-PPAR介导的他汀类药物的活性以及AMP激活的蛋白激酶(AMPK)的激活对EAE中的少突胶质细胞的炎性损伤具有保护作用，洛伐他汀与AMPK的特异性激活剂AICAR的联合应用显著提高了对EAE疾病的疗效，从而表明这些药物对EAE的中枢神经系统疾病有潜在的疗效。AMPK是一种细胞能量感受器，在过氧化物体和线粒体的生物发生、动力学和自噬清除中发挥着重要作用。此外，最近一项对140名进展型MS患者进行的II期双盲安慰剂对照研究报告称，辛伐他汀治疗脑萎缩在两年内减少了50%，这也支持了他汀类药物对MS中枢神经系统疾病的疗效。基于这些发现，我们假设靶向RhoA-Rock-PPAR信号机制(洛伐他汀)和AMPK/PGC-1AICAR信号机制的药物在EAE/MS疾病中提供了更好的神经保护和加速神经修复，从而提高了EAE/MS的疗效。这项拟议的研究将使用培养的神经元和少突胶质细胞在EAE疾病条件下以及EAE小鼠模型来研究线粒体和过氧化体异常的机制。目的：探讨EAE条件下培养的神经元和少突胶质细胞线粒体和过氧化物体的生物发生和自噬清除的机制。目的：评价RhoA/PPAR介导的洛伐他汀和AMPK/PGC-1α介导的机制对EAE小鼠的神经保护和神经修复的治疗作用。这项研究的新颖性是针对EAE和MS的中枢神经系统疾病机制的新治疗方法的前提。拟议的研究将使用最先进的方法来解决拟议的目标。他汀类药物是治疗高胆固醇血症最常用的药物，因此，单用他汀类药物或与AMPK激活剂联合使用这种新型口服疗法的翻译潜力相当高。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory demyelinating disease leading to loss of oligodendrocytes, myelin and axons and neurodegenerative lesion formation. Present day drugs developed to target immunomodulatory mechanisms provide limited efficacy since CNS disease progression continues despite treatment. Studies from various laboratories including ours have provided evidence of functional abnormality of mitochondria and peroxisomes as a cause of CNS disease pathologies in EAE (experimental autoimmune encephalomyelitis) and MS but very little, if any, about the mechanisms leading to these pathologies. The present proposal is designed to understand the mechanisms of mitochondrial and peroxisomal dysfunction and to determine the efficacy of drugs targeting these pathologies for neuroprotection and neurorepair in EAE. Recently, we have described that RhoA-Rock-PPAR mediated activity of statins as well as activation of AMP activated protein kinase (AMPK) protects oligodendrocytes against inflammatory insult in EAE and that a combination of lovastatin and AICAR, a specific activator AMPK, greatly improved the efficacy against EAE disease thus indicating the potential efficacy of these drugs against the CNS disease of EAE. AMPK is a cellular energy sensor playing an essential role in biogenesis, dynamics, and autophagic clearance of peroxisomes and mitochondria. Moreover, a recent phase-II double blind placebo controlled study of 140 patients with the progressive form of MS, a disease with no approved drug, reporting efficacy of simvastatin treatment as 50% reduction in brain atrophy over two years also supports the efficacy of statins against CNS disease of MS. Based on these findings, we hypothesize that drugs targeting RhoA-Rock-PPAR signaling mechanisms (lovastatin) and AMPK/PGC-1α-mTOR signaling mechanisms with AMPK activator (AICAR) in EAE/MS disease provides greater neuroprotection and accelerated neurorepair and hence improved efficacy in EAE/MS. Therefore, the proposed studies will investigate the mechanisms underlying mitochondrial and peroxisomal abnormalities using both cultured neurons and oligodendrocytes under EAE disease conditions, and mouse models of EAE. Aim 1: To investigate the mechanisms of mitochondrial and peroxisomal biogenesis and autophagic clearance in cultured neurons and oligodendrocytes under EAE conditions. Aim 2: To evaluate the therapeutic potential of RhoA/PPAR-mediated mechanisms using lovastatin and AMPK/PGC-1α-mediated mechanisms using AICAR for neuroprotection and neurorepair in EAE mice. The novelty of the study is the premise of a new therapeutic approach targeting CNS disease mechanisms of EAE and MS. The proposed studies will use state-of-the-art methodologies to address the proposed goals. Statins are the most commonly used drugs for hypercholesterolemia; therefore, translational potential of such a novel oral therapy of statin alone or in combination with activator of AMPK is reasonably high.