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: 8242616
• 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/8242616
• 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; public health relevance; 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）是中枢神经系统（CNS）炎症性脱髓鞘疾病，影响最具生产力年龄的个体。MS在美国退伍军人中普遍存在，这是由于他们在服役期间的先前居住地或社会经济状况，因为风险因素在北方轮胎州比南方轮胎州更多。到目前为止，MS缺乏有效的治疗方法：目前FDA批准的药物专注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。本提案计划在MS的实验性自身免疫性脑脊髓炎（EAE）模型中，在少突胶质细胞（OP）祖细胞（OPC）的存活和分化的背景下，评估AMP活化蛋白激酶（AMPK）的作用，AMPK是一种遗传学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。AMPK先前已涉及神经元对各种炎症损伤的保护和分化。具体而言，AMPK已经在EAE中的髓鞘修复和神经保护方面进行了研究。数据表明，OPCs分化为髓鞘形成OL是必不可少的髓鞘修复和维护在中枢神经系统脱髓鞘疾病。我们最近的研究证实，5-氨基咪唑-4-甲酰胺-1-2-D-呋喃核糖苷（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基因敲除小鼠比野生型小鼠具有更严重的EAE，表明AMPK在EAE减弱中的作用。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是明显的。 最近的研究证实AMPK在各种细胞类型中对过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）活性的调节是重要的，这归因于直接的过氧化物酶体增殖物激活受体磷酸化或其内源性激活剂的生物利用度增加。PPARs是调节各种细胞类型的生长和分化的核受体。与AMPK类似，据报道，作为免疫调节和BBB保护活性的函数，PPAR活化参与EAE的减弱，而炎症反应倾向于下调PPAR细胞表达。重要的是，已显示PPAR活化诱导OPC分化为髓鞘形成OL。基于这些研究，我们推测活化的AMPK介导的PPAR活性调节可能参与OPCs的分化以促进EAE中的髓鞘修复。阐明这一机制将使我们能够设计新的治疗方法，以促进髓鞘修复和限制MS在受影响的个体中的进展。因此，该建议的重点将是确定使用活化的AMPK在OPCs中调节PPAR亚型活性，这可能参与它们的存活和分化（目的1）。接下来，我们将在治疗上评估AMPK激活剂二甲双胍单独或与PPAR亚型激动剂组合以促进EAE模型中的神经修复（目的2）。 这项研究的新奇是新的治疗靶点，用于诱导髓鞘修复，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是一种创新方法。 公共卫生相关性： MS在美国退伍军人中高度流行，这是由于他们在服役期间的先前居住地或社会经济状况，因为风险因素在美国北方轮胎州比南方轮胎州更多。流行病学研究表明，在所有参加过二战、朝鲜战争和1991年海湾战争的退伍军人中，MS的发生率很高，这与环境因素或疾病的沉淀有关。因此，需要一种有效的MS治疗方法来治疗在伊拉克和阿富汗的战争时期和不同环境条件下工作的退伍军人。尽管目前针对MS的治疗靶向免疫应答，但该疾病通常进展导致脱髓鞘，从而导致受影响个体的身体残疾。缺乏有效的治疗MS代表了一个显着的差距控制it.So，在少突胶质细胞祖细胞中二甲双胍的AMPK介导的PPARs的调节机制的理解将确定新的治疗诱导髓鞘修复（髓鞘再生）通过靶向MS患者的内源性前体细胞。