Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis

多发性硬化症的神经保护和髓磷脂修复机制

• 批准号: 8044323
• 负责人: Inderjit Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044323
• 关键词: 5' -AMP-activated protein kinase; Affect; Afghanistan; Age; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Attenuated; Axon; Blood - brain barrier anatomy; Brain; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Cycle Arrest; Data; Demyelinating Diseases; Demyelinations; Development; Differentiation and Growth; Disease; Endotoxemia; Environmental Risk Factor; Epidemiologic Studies; Experimental Autoimmune Encephalomyelitis; FDA approved; Genes; Geographic state; Glucose; Glutamates; Gulf War; Helper-Inducer T-Lymphocyte; Homeostasis; Immune response; Immunosuppression; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Iraq; Knockout Mice; Korean War; Laboratories; Lesion; Lipopolysaccharides; Maintenance; Mediating; Metabolic; Metformin; Modeling; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neuronal Differentiation; Neurons; Nuclear Receptors; Oligodendroglia; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phosphorylation; Precipitation; Prevention; Process; Receptor Activation; Regulation; Reporting; Risk Factors; Role; Services; Socioeconomic Status; Stem cells; Testing; Therapeutic; Time; Treatment Efficacy; Veterans; War; Wild Type Mouse; Work; World War II; attenuation; base; cell type; central nervous system demyelinating disorder; deprivation; design; disability; effective therapy; excitotoxicity; glucose metabolism; immunoregulation; improved; injured; innovation; lipid metabolism; myelin degeneration; neuron loss; neuroprotection; new therapeutic target; novel therapeutics; precursor cell; remyelination; repaired; residence; response; sensor; therapeutic target

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is central nervous system (CNS) inflammatory, demyelinating disease that affects individuals in their most productive ages. MS is prevalent in US veterans due to their prior residence or socioeconomics status during their service as risk factor is more in northern tire states than southern tire states. So far MS lacks effective treatment: current FDA-approved drugs focus on attenuating the progression of peripheral immune responses and do not emphasize neuro-repair in the injured brain. The present proposal is planned to evaluate the role of AMP-activated protein kinase (AMPK), a phylogenetically conserved, intracellular energy sensor switch which helps regulate glucose and lipid metabolism, in the context of the survival and differentiation of oligodendrocyte (OP) progenitor cells (OPCs) in an experimental autoimmune encephalomyelitis (EAE) model of MS. In line with this, AMPK has previously been implicated in the protection and differentiation of neurons against various inflammatory insults. Specifically, AMPK has been studied with respect to myelin repair and neuroprotection in EAE. Data suggest that the differentiation of OPCs into myelin-forming OLs is essential for myelin repair and maintenance during CNS demyelinating diseases. Our recent studies established that AMPK activation by 5-aminoimidazole-4-carboxamide-1-2-D-ribofuranoside (AICAR) or metformin attenuates EAE disease and provides neuro-protection via immunomodulation and protection of the blood brain barrier (BBB). Moreover, AMPK-11 gene knockout mice had more severe EAE than wild-type mice, suggesting a role for AMPK in EAE attenuation. These anti-inflammatory activities of AMPK were also evident in lipopolysaccharide (LPS)-stimulated astrocytes in vitro as well as in endotoxemia model. Recent studies established that AMPK is important in the regulation of peroxisome proliferator-activated receptor (PPAR) activity in various cell types and this was ascribed to direct PPAR phosphorylation or increased bio-availability of their endogenous activators. PPARs are nuclear receptors which regulate the growth and differentiation of various cell types. Similar to AMPK, PPAR activation is reported to participate in the attenuation of EAE as a function of immunomodulatory and BBB protection activities, whereas the inflammatory response tends to downregulate PPAR cellular expression. Importantly, PPAR activation has been shown to induce the differentiation of OPCs into myelin-forming OLs. Based upon these studies, we hypothesized that activated AMPK-mediated regulation of PPAR activity may participate in the differentiation of OPCs to promote myelin repair in EAE. Elucidation of this mechanism will permit us to design new therapeutics to promote myelin repair and limit the progression of MS in affected individuals. Therefore, the focus of this proposal will be to determine the regulation of PPAR subtype activity using activated AMPK in OPCs, which may participate in their survival and differentiation (Aim 1). Next we will therapeutically evaluate the AMPK activator metformin alone or in combination with an agonist of PPAR subtypes to promote neuro-repair in an EAE model (Aim 2). The novelty of the study is the promise of 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 an innovative approach. PUBLIC HEALTH RELEVANCE: MS is highly prevalent in US veterans due to their prior residence or socioeconomics status during their service as risk factor is more in northern tire states than southern tire states of US. Epidemiological studies demonstrated that the high rate of MS occurrence in all veterans who served in World War II, the Korean conflict and the Gulf war in 1991 due to the environmental factors or the precipitation of the disease. Therefore, an effective therapy for MS is required to treat veterans working at this time period of war and different environmental conditions in Iraq and Afghanistan. In spite of the current therapeutics for MS targeting immune response, the disease often progresses leading to demyelination thus physical disability in affected individuals. Lack of effective treatment for MS represents a significant gap for controlling it. Therefore, the understanding of proposed mechanism of AMPK mediated regulation of PPARs by metformin in oligodendrocyte progenitor cells will identify novel therapeutic for induction of myelin repair (remyelination) by targeting the endogenous precursor cells in MS patients.

描述（由申请人提供）： 多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病，影响处于生产力最高年龄的个体。由于美国退伍军人之前的居住地或服役期间的社会经济状况，多发性硬化症在美国退伍军人中很普遍，因为北方轮胎州的风险因素比南方轮胎州更多。到目前为止，多发性硬化症缺乏有效的治疗方法：目前 FDA 批准的药物侧重于减弱外周免疫反应的进展，而不强调受损大脑的神经修复。目前的提案计划评估 AMP 激活蛋白激酶 (AMPK) 的作用，AMPK 是一种系统发育保守的细胞内能量传感器开关，有助于调节葡萄糖和脂质代谢，在少突胶质细胞 (OP) 祖细胞的存活和分化的背景下(OPC) 在 MS 实验性自身免疫性脑脊髓炎 (EAE) 模型中的应用。与此相一致的是，AMPK 此前曾被认为与神经元对抗各种炎症损伤的保护和分化有关。具体来说，AMPK 已在 EAE 中的髓磷脂修复和神经保护方面进行了研究。数据表明，OPCs 分化为髓磷脂形成 OLs 对于中枢神经系统脱髓鞘疾病期间髓磷脂的修复和维持至关重要。我们最近的研究表明，5-氨基咪唑-4-甲酰胺-1-2-D-呋喃核苷 (AICAR) 或二甲双胍激活 AMPK 可减轻 EAE 疾病，并通过免疫调节和保护血脑屏障 (BBB) 提供神经保护。此外，AMPK-11 基因敲除小鼠的 EAE 比野生型小鼠更严重，表明 AMPK 在 EAE 减弱中发挥作用。 AMPK 的这些抗炎活性在体外脂多糖 (LPS) 刺激的星形胶质细胞以及内毒素血症模型中也很明显。 最近的研究表明，AMPK 在调节各种细胞类型中的过氧化物酶体增殖物激活受体 (PPAR) 活性方面​​发挥着重要作用，这归因于 PPAR 的直接磷酸化或其内源性激活剂的生物利用度增加。 PPAR 是调节各种细胞类型生长和分化的核受体。与 AMPK 类似，据报道，PPAR 激活作为免疫调节和 BBB 保护活性的功能参与 EAE 的减弱，而炎症反应往往会下调 PPAR 细胞表达。重要的是，PPAR 激活已被证明可诱导 OPC 分化为形成髓磷脂的 OL。基于这些研究，我们假设激活的 AMPK 介导的 PPAR 活性调节可能参与 OPC 的分化，从而促进 EAE 中的髓磷脂修复。阐明这一机制将使我们能够设计新的疗法来促进髓磷脂修复并限制受影响个体的多发性硬化症进展。因此，本提案的重点是确定 OPC 中激活的 AMPK 对 PPAR 亚型活性的调节，这可能参与 OPC 的生存和分化（目标 1）。接下来，我们将在 EAE 模型中单独评估 AMPK 激活剂二甲双胍或与 PPAR 亚型激动剂联合使用以促进神经修复（目标 2）。 该研究的新颖之处在于有望找到诱导髓磷脂修复的新治疗靶点，以改善多发性硬化症等神经退行性疾病的治疗和管理。炎症脱髓鞘模型中神经细胞机制的治疗靶向是一种创新方法。 公共卫生相关性： 由于美国退伍军人之前的居住地或服役期间的社会经济状况，多发性硬化症在美国退伍军人中非常普遍，因为美国北部轮胎州的风险因素比南部轮胎州更高。流行病学研究表明，由于环境因素或疾病沉淀，参加过二战、朝鲜冲突和1991年海湾战争的所有退伍军人中MS的发病率较高。因此，需要一种有效的多发性硬化症治疗方法来治疗在战争时期以及伊拉克和阿富汗不同环境条件下工作的退伍军人。尽管目前多发性硬化症的治疗方法以免疫反应为目标，但该疾病往往会进展，导致脱髓鞘，从而导致受影响个体的身体残疾。多发性硬化症缺乏有效的治疗方法，在控制多发性硬化症方面存在巨大差距。因此，了解少突胶质细胞祖细胞中二甲双胍介导的 AMPK 介导的 PPAR 调节机制将确定通过靶向多发性硬化症患者的内源性前体细胞来诱导髓磷脂修复（髓鞘再生）的新疗法。