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: 8597413
• 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/8597413
• 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，会影响其生产力最高的人。 MS在美国退伍军人服务期间的先前居住或社会经济状况在北部轮胎州比南部轮胎州更重要。到目前为止，MS缺乏有效的治疗方法：当前的FDA批准药物专注于减轻周围免疫反应的进展，并且不强调受伤的大脑中的神经修复。 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.与此相一致，AMPK以前涉及神经元免受各种炎症性侮辱的保护和分化。具体而言，已经研究了AMPK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，在中枢神经系统脱髓鞘疾病期间，OPC将OPC分化为形成髓磷脂的OL对于髓磷脂修复和维护至关重要。我们最近的研究表明，5-氨基咪唑-4-羧化酰胺-1-2-D-核苷二 - 核苷（AICAR）或二甲双胍激活AMPK激活EAE病，并通过对血液脑屏障（BBB）的免疫调节和保护提供神经保护。此外，AMPK-11基因基因敲除小鼠比野生型小鼠更严重，这表明AMPK在EAE衰减中起作用。 AMPK的这些抗炎活性在脂多糖（LPS）刺激的体外和内毒素模型中也很明显。 最近的研究表明，AMPK在各种细胞类型中的过氧化物酶体增殖物激活受体（PPAR）活性中很重要，这被归因于其内源性激活剂的PPAR磷酸化或增加的生物利用度。 PPAR是调节各种细胞类型的生长和分化的核受体。与AMPK相似，据报道PPAR激活参与EAE的衰减，这是免疫调节和BBB保护活动的函数，而炎症反应倾向于下调PPAR细胞表达。重要的是，已证明PPAR激活诱导OPC的分化为髓磷脂形成OLS。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的分化以促进EAE中的髓磷脂修复。阐明这种机制将使我们能够设计新的治疗剂，以促进髓磷脂修复并限制受影响个体中MS的进展。因此，该提案的重点将是使用OPC中激活的AMPK来确定PPAR亚型活性的调节，OPC可能参与其生存和分化（AIM 1）。接下来，我们将单独评估AMPK激活剂二甲双胍或与PPAR亚型激动剂结合使用，以在EAE模型中促进神经修复（AIM 2）。 该研究的新颖性是新的治疗靶标有望诱导髓磷脂修复，以改善治疗和管理神经退行性疾病（例如MS）。炎症性脱髓鞘模型中神经细胞机制的治疗靶向是一种创新的方法。 公共卫生相关性： MS在美国退伍军人服务期间的先前居住或社会经济状况在北部轮胎状态中比我们南部轮胎状态更为普遍。流行病学研究表明，由于环境因素或疾病的降水，在第二次世界大战，朝鲜冲突和海湾战争中服役的所有退伍军人的MS发生率很高。因此，需要对MS进行有效的疗法来治疗在这段战争期间工作的退伍军人以及伊拉克和阿富汗的不同环境条件。尽管当前针对MS靶向免疫反应的治疗剂，但该疾病通常会导致脱髓鞘，因此受影响的个体的身体残疾。缺乏有效的MS处理是控制它的显着差距。因此，通过二甲双胍在少突胶质细胞祖细胞中对AMPK介导的PPAR的提出机制的理解将通过靶向MS患者的内源性前体细胞来鉴定新的治疗方法，以诱导髓磷脂修复（Remyelination）。