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: 8391637
• 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/8391637
• 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.

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，影响个人在最具生产力的年龄。多发性硬化症在美国退伍军人中普遍存在，这是由于他们以前的居住地或服役期间的社会经济地位，因为风险因素在北部轮胎州比南部轮胎州更多。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缓外周免疫反应的进展，而不是强调受伤大脑的神经修复。本研究拟在实验性自身免疫性脑脊髓炎(EAE)MS模型中评估AMP激活蛋白激酶(AMPK)在少突胶质细胞(OP)祖细胞(OPC)存活和分化中的作用。AMPK是一种系统发育保守的细胞内能量感受器开关，有助于调节糖和脂代谢。具体来说，AMPK在EAE的髓鞘修复和神经保护方面已经被研究过。资料表明，在中枢神经系统脱髓鞘疾病中，OPC分化为髓鞘形成的OL对于髓鞘的修复和维持至关重要。我们最近的研究证实，5-aminoimidazole-4-carboxamide-1-2-D-ribofuranoside(AICAR)或二甲双胍激活AMPK可以减轻EAE疾病，并通过免疫调节和保护血脑屏障提供神经保护。此外，AMPK-11基因敲除小鼠比野生型小鼠有更严重的EAE，提示AMPK在EAE减毒中起作用。在脂多糖刺激的星形胶质细胞和内毒素血症模型中，AMPK的这些抗炎活性也是明显的。最近的研究表明，AMPK在不同类型细胞中对PPAR活性的调节是重要的，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的提高。PPAR是一种核受体，调节各种类型细胞的生长和分化。与AMPK相似，PPAR的激活被报道作为免疫调节和BBB保护活动的功能参与了EAE的减弱，而炎症反应往往下调PPAR细胞的表达。重要的是，PPAR的激活已被证明可以诱导OPC分化为髓鞘形成的OL。基于这些研究，我们推测激活的AMPK介导的PPAR活性调节可能参与了OPC的分化，以促进EAE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来促进髓鞘修复并限制受影响个体的多发性硬化的进展。因此，这项建议的重点将是确定在OPC中使用激活的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，我们将对AMPK激活剂二甲双胍单独或与PPAR亚型激动剂联合使用以促进EAE模型中的神经修复进行治疗学评估(目标2)。这项研究的新颖性在于有望通过诱导髓鞘修复来改善神经退行性疾病(如MS)的治疗和管理。针对炎性脱髓鞘模型中的神经细胞机制进行靶向治疗是一种创新的方法。