Cytokines in Glial Cells and EAE Brain

描述（由申请人提供）：多发性硬化（MS）是一种炎性脱髓鞘疾病，缺乏有效的治疗，因为目前靶向免疫抑制的MS药物对中枢神经系统（CNS）疾病的获益有限（如果有的话），中枢神经系统（CNS）疾病继续进展。该提议旨在研究靶向Rho家族GTP酶（RFG）的药物在EAE/MS的CNS中诱导内源性髓鞘修复机制的潜力。来自我们实验室和其他人的先前研究已经证明，类异戊二烯介导的用他汀类调节RFG在实验性自身免疫性脑脊髓炎（EAE）中提供免疫调节和血脑屏障保护活性，我们最近的研究提供了RFG介导的机制参与神经保护的证据，如EAE中脱髓鞘减少（髓鞘蛋白和脂质两者的损失）和OL祖细胞的损失所揭示的。此外，混合神经胶质细胞培养物的体外研究证明，RFG介导的机制也可能潜在地提供早髓鞘形成作用，如少突胶质细胞（OL）祖细胞的存活和分化增强所证明的。重要的是，他汀类药物的这些作用归因于细胞内类异戊二烯的特异性消耗，而不是细胞或CNS中胆固醇的水平。此外，在EAE的CNS中观察到过氧化物酶体增殖物激活受体（PPARs）的水平降低以及它们通过他汀类药物的正常化和激活表明他汀类药物-RFGs介导的机制可以调节PPARs的细胞内稳态。基于这些信息，我们假设他汀类药物介导的RFG调节可能调节OL祖细胞中的PPARs活性，以促进其分化为EAE动物CNS中的髓鞘再生OL。以下研究旨在验证这一假设。具体目标1：探讨RFGs对体外培养的OL-祖细胞存活和分化的PPARs活化的调控机制。具体目标2：评价RFG诱导的PPARs活性在EAE炎症性脱髓鞘模型中诱导髓鞘修复的意义。该研究的新奇在于确定诱导髓鞘修复的新治疗靶点，以改善神经退行性疾病（如MS）的治疗和管理。在炎症性脱髓鞘模型中靶向神经细胞机制的治疗本质上是一种创新方法。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS), an inflammatory demyelinating disease, lacks effective treatment because the current MS drugs targeting immunosuppression provide limited, if any, benefit to the central nervous system (CNS) disease where it continues to progress. This proposal is designed to investigate the potential of drugs targeting the Rho family GTPases (RFGs) for induction of endogenous myelin repair mechanisms in the CNS of EAE/MS. Previous studies from our laboratory and others have demonstrated that isoprenoids mediated regulation of RFGs with statins provides immunomodulatory and blood-brain-barrier protection activities in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our recent studies provide evidence for involvement of RFGs mediated mechanisms in neuroprotection as revealed by reduced demyelination (loss of both myelin proteins and lipids) and loss of OL-progenitors in EAE. Moreover, in vitro studies with mixed glial cultures document that RFGs mediated mechanisms may also potentially provide promyelinating effects as evidenced by enhanced survival and differentiation of oligodendrocyte (OL)-progenitors. Importantly, these effects of statins were attributed to be the specific depletion of intracellular isoprenoids rather than the level of cholesterol in the cells or CNS. Moreover, the observed reduced levels of peroxisome proliferator activated receptors (PPARs) in the CNS of EAE and their normalization and activation by statin indicates that statin-RFGs mediated mechanisms may regulate the cellular homeostasis of PPARs. Based on this information, we hypothesize that statin mediated regulation of RFGs may modulate PPARs activities in OL-progenitors to promote their differentiation into remyelinating OLs in the CNS of EAE animals. The following studies are proposed to test this hypothesis. Specific aim 1: To investigate the RFGs mediated regulatory mechanisms for PPARs activation for the survival and differentiation of OL-progenitors in vitro cell culture systems. Specific aim 2: To evaluate the significance of RFGs induced PPARs activities in the induction of myelin repair in the inflammatory demyelinating model of EAE. The novelty of the study is to identify new therapeutic targets for induction of myelin repair for improved treatment and management of neurodegenerative diseases such as MS. Therapeutic targeting of neural cell mechanisms in inflammatory demyelinating model is essentially an innovative approach.