Aspirin, PPAR and EAE

阿司匹林、PPAR 和 EAE

基本信息

批准号：
8974336
负责人：
KALIPADA PAHAN
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8974336
关键词：
Air Pollutants Analgesics Animal Model Anthrax disease Anti-Inflammatory Agents Anti-inflammatory Aspirin Astrocytes Autoimmune Process Blood Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor CREB1 gene Caucasians Central Nervous System Viral Diseases Chemicals Chronic Ciliary Neurotrophic Factor Clinical Demyelinating Diseases Demyelinations Diagnosis Disease Dose Drug usage European Experimental Autoimmune Encephalomyelitis Exposure to Family Genes Grant Gulf War Health Hepatitis B Human IL6ST gene Incidence Infiltration Inflammation Inflammatory Injection of therapeutic agent Interleukin-11 LIF gene Link Mediating Molecular Multiple Sclerosis Mus Myelin NF-kappa B Neurology Oral Oral Administration Outcome Pathway interactions Permeability Peroxisome Proliferator-Activated Receptors Process Production Property Relapse Research Risk Services Spinal Cord Symptoms Testing Therapeutic Toxin United States Up-Regulation Vaccination Veterans Vietnam Virus Diseases War anakinra axon injury combat cytokine effective therapy glial cell-line derived neurotrophic factor multiple sclerosis patient neurotrophic factor neurotrophin 4 neurturin novel remyelination repaired

项目摘要

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic human demyelinating disorder of the CNS having an autoimmune connection. At present, about 400,000 people in the United States have MS. It is more common among Caucasians, particularly those of northern European ancestry. Several evidences show a potential link between the incidence of MS and combat service. For example, one study in the Annals of Neurology (2004, 55: 65-71) has identified 5,345 cases of MS among U.S. veterans that were deemed "service-connected." Although the mechanism is not clear, viral infections, several vaccinations and exposure to different war zone chemicals may increase the risk of having MS. Accordingly, several veterans who served Gulf war 1 as well as many Vietnam veterans have been diagnosed with MS. In spite of extensive research, no effective therapy is available to halt the progression of MS. Inflammation and demyelination are major pathological features of MS and experimental allergic encephalomyelitis (EAE), an animal model of MS. Therefore, suppressing inflammation and promoting remyelination, appear to be crucial therapeutic challenges for MS. While neurotrophins (NGF, NT-3, NT-4/5, and BDNF) and glial cell line-derived neurotrophic factor (GDNF)-related factors (GDNF, neurturin) do not increase myelinogenesis, ciliary neurotrophic factor (CNTF) induces a strong promyelinating effect. Therefore, increasing the level of CNTF in the CNS is an important step in repairing axonal damage in MS. Although gene manipulation and stereotaxic injection of CNTF into the brain are available options, it seems from the therapeutic angle, the best option is to stimulate/induce the production of CNTF within the CNS of patients with MS. Is it really possible? Our preliminary results show that it is possible with aspirin, acetylsalicylic acid, one f the most widely-used analgesics throughout the world. We have discovered that aspirin increases myelinogenic trophic factor CNTF and upregulates anti-inflammatory molecules in astrocytes via involving different peroxisome proliferator-activated receptors (PPARs). Furthermore, oral administration of aspirin reduces clinical symptoms of EAE. This grant is anchored to these exciting findings. From the academic angle, we have dedicated Specific aims I and II to investigate molecular mechanisms behind these novel trophic and anti-inflammatory efficacies of aspirin. From the therapeutic angle, we will test the effect of aspirin on myelinatio and anti-inflammation and the overall disease process of relapsing-remitting, chronic and spontaneous EAE in mice under Specific aim III. A positive outcome will highlight undiscovered properties of aspirin and enhance the possibility of controlling MS by this widely-used drug.

描述（由申请人提供）：多发性硬化症（MS）是具有自身免疫连接的中枢神经系统的慢性人类脱髓鞘障碍。目前，美国约有40万人有MS。在高加索人，尤其是北欧血统的高加索人中，它更为普遍。几个证据表明MS的发生率与战斗服务之间存在潜在的联系。例如，《神经病学史》中的一项研究（2004，55：65-71）在美国退伍军人中发现了5,345例MS病例，这些病例被认为是“与服务相关”。尽管该机制尚不清楚，但病毒感染，几种疫苗接种和接触不同的战区化学物质可能会增加患有MS的风险。因此，为海湾1战争1的资深人士以及许多越南退伍军人被诊断出患有MS。尽管进行了广泛的研究，但尚无有效的疗法来阻止MS的进展。炎症和脱髓鞘是MS的主要病理特征和MS动物模型的实验过敏性脑脊髓炎（EAE）。因此，抑制炎症并促进透明度，对于MS来说似乎是至关重要的治疗挑战。而神经营养蛋白（NGF，NT-3，NT-4/5和BDNF）和神经胶质细胞系衍生的神经营养因子（GDNF）相关因子（GDNF，Neurturin）并没有增加髓质性神经营养因子（CNTF），这会引起肌基神经亲子因子（CNTF）的强烈效果。因此，增加中枢神经系统中的CNTF水平是修复MS中轴突损伤的重要步骤。尽管CNTF的基因操纵和立体定位注射到大脑中是可用的选择，但从治疗角度看来，最好的选择是刺激/诱导MS患者CNS中CNTF的产生。真的有可能吗？我们的初步结果表明，阿司匹林，乙酰水杨酸酸是可能的，这是全球最广泛使用的镇痛药。我们已经发现，阿司匹林通过涉及不同的过氧化物酶体增殖物激活受体（PPAR）来增加髓纤维营养因子CNTF并上调星形胶质细胞中的抗炎分子。此外，阿司匹林口服给药可减少EAE的临床症状。这笔赠款奠定了这些令人兴奋的发现。从学术角度来看，我们具有专门的特定目的I和II来研究这些新型营养和抗炎作用的分子机制。从治疗角度来看，我们将测试阿司匹林对特定AIM III下小鼠中骨髓和抗炎的影响以及整体疾病的复发，慢性和自发EAE的作用。积极的结果将突出阿司匹林未被发现的特性，并通过这种广泛使用的药物来控制MS的可能性。