Cytokines in Glial Cells and EAE Brain

神经胶质细胞和 EAE 脑中的细胞因子

• 批准号: 8013818
• 负责人: Inderjit Singh
• 金额: $ 31.62万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013818
• 关键词: Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autoimmune Process; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; CD4 Positive T Lymphocytes; Cell Culture System; Cells; Central Nervous System Diseases; Cholesterol; Chronic; Ciliary Neurotrophic Factor; Complement; Copaxone; Demyelinating Diseases; Demyelinations; Development; Disease; Disease model; Drug Delivery Systems; Event; Experimental Autoimmune Encephalomyelitis; Family; Farnesyl Transferase Inhibitor; Glial Growth Factor; Guanosine Triphosphate Phosphohydrolases; Helper-Inducer T-Lymphocyte; Homeostasis; Immune; Immune response; Immunosuppression; In Vitro; Individual; Inflammatory; Insulin-Like Growth Factor I; Interferons; Interleukins; LIF gene; Laboratories; Lesion; Lipids; Lovastatin; Low Density Lipoprotein Receptor; Maintenance; Mediating; Modeling; Monomeric GTP-Binding Proteins; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myelin Associated Glycoprotein; Myelin Basic Proteins; Myelin Proteins; NRG1 gene; Necrosis; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Oligodendroglia; PGGT1B gene; PTEN gene; PTGS2 gene; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phospholipase; Phosphoric Monoester Hydrolases; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Property; Proteins; Proteolipids; Receptor Activation; Regulation; Relapse; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; Signal Pathway; Signal Transduction; Spinal Cord; TNF gene; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Suppression; arm; base; brain-derived growth factor; central nervous system demyelinating disorder; central nervous system injury; cyclooxygenase 2; cytokine; design; disability; drug candidate; effective therapy; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; glycerone-phosphate O-acyltransferase; improved; inhibitor/antagonist; innovation; isoprenoid; leukemia; mevalonate; mouse model; myelin degeneration; neuroprotection; new therapeutic target; novel; oligodendrocyte-myelin glycoprotein; open label; precursor cell; progenitor; protein geranylgeranyltransferase; public health relevance; repaired; rho; tensin; therapeutic target; tumor

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. PUBLIC HEALTH RELEVANCE: MS an autoimmune inflammatory demyelinating disease, affects approximately 400,000 individuals in US only and over 2.0 million individuals worldwide. In spite of the current therapeutics targeting immune response, the disease often progresses leading to neurodegeneration and thus physical disability reflecting the CNS injury. Therefore, the lack of effective treatments for MS represents a significant gap for treating the CNS disease. In addition to the anti-inflammatory and immunomodulatory properties the recently observed neuroprotective activities of statins identify novel aspect of their mechanisms for myelin repair by targeting the endogenous precursor cell. The proposed studies are innovative as they will improve our understanding of mechanisms for pharmacological enhancement of the potential of CNS endogenous cells to treat CNS disease (myelin repair) in MS. These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases.

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：探讨RFG诱导的PPARs活性在诱导EAE炎性脱髓鞘模型髓鞘修复中的意义。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。 公共卫生关系：MS是一种自身免疫性炎性脱髓鞘疾病，仅在美国影响约40万个体，在全球影响超过200万个体。尽管目前的治疗靶向免疫应答，但该疾病通常进展导致神经变性，从而导致反映CNS损伤的身体残疾。因此，缺乏有效的MS治疗代表了治疗CNS疾病的显著差距。除了抗炎和免疫调节特性外，最近观察到的他汀类药物的神经保护活性通过靶向内源性前体细胞确定了其髓鞘修复机制的新方面。拟议的研究是创新的，因为它们将提高我们的药理学增强机制的潜力，中枢神经系统内源性细胞治疗中枢神经系统疾病（髓鞘修复）在MS。这些研究将确定诱导髓鞘修复MS的治疗靶点，这些发现应适用于其他相关的神经退行性疾病。