Use of Resveratrol to treat experimental multiple sclerosis

使用白藜芦醇治疗实验性多发性硬化症

• 批准号: 7394180
• 负责人: Prakash S Nagarkatti
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394180
• 关键词: Acute; Address; Adjuvant; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Aryl Hydrocarbon Receptor; Autoantigens; Autoimmune Diseases; CD44 gene; Cardiovascular Diseases; Cell Line; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Clinical; Demyelinations; Dendritic Cells; Diagnosis; Dioxins; Disease; Down-Regulation; Elements; Encephalomyelitis; Estrogen Receptors; Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Functional disorder; Gene Expression; Genes; Grapes; Heterogeneity; Homing; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Induction of Apoptosis; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Knockout Mice; Life; Luc Gene; Mediating; Modality; Morus; Multiple Sclerosis; Mus; Myelin; Myelin Basic Proteins; Nerve Degeneration; Neuraxis; Paralysed; Pathway interactions; Peanuts - dietary; Peripheral; Pharmaceutical Preparations; Plants; Play; Principal Investigator; Promoter Regions; Property; Proteins; Proteolipids; Relapse; Reporter; Reporter Genes; Resveratrol; Rodent Model; Role; Side; Site-Directed Mutagenesis; Symptoms; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Transfection; Up-Regulation; autocrine; cyclooxygenase 2; deletion analysis; disability; disorder control; in vivo; insight; novel; oligodendrocyte-myelin glycoprotein; paracrine; polyphenol; prevent; programs; promoter; receptor; response; transcription factor; young adult

Multiple Sclerosis (MS) is an autoimmune disease that affects ~400,000 people in the US. It is a life-long chronic disease diagnosed primarily in young adults. There is, as yet no cure for MS. The current treatment includes use of immunosuppressive drugs that often exhibit toxic side effects.Thus, there is a pressing need for alternate and more effective treatment strategies that target the components of inflammatory cells. CAM therapies constitute an important strategy to treat and control the disease. Experimental autoimmune encephalomyelitis is an animal model of MS induced by injection of self antigens, myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein and adjuvants. Resveratrol (RES; 3,5,4'- trihydroxystilbene), a nonflovaonoid polyphenol found in various plants including mulberries, peanuts and grapes has been shown to have beneficial effects particularly on cardiovascular diseases through its antiinflammatory properties. Our Preliminary Studies have demonstrated that RES induces apoptosis primarily in activated T cells through Fas-FasL interactions, involving aryl hydrocarbon receptor (AhR) and estrogen receptor (ER). Moreover, in vivo, RES down regulates CD44 and upregulates FoxpS. We are also excited by our findings that RES treatment decreases the inflammation and clinical symptoms of EAE. In the current study, we will test the central hypothesis that RES treatment is effective against EAE through multiple pathways incuding induction of apoptosis in myelin-specific T cells, suppression of DC functions, decreased T cell infiltration in the CMS due to CD44 down-regulation on T cells, and upregulation of T regs. We will pursue the specific aims: # 1. Study the role of Fas-FasL interactions in resveratrol (RES)-induced apoptosis in T cells and dendritic cells (DCs) involving autocrine or paracrine path ways.#2. Investigate the role of AhR in Fas-FasL upregulation and consequent apoptosis induced by RES in T cells.tf 3. Test the role of ER in the induction of apoptosis in T cells and peripheral T dysfunction following RES treatment.^ 4. Study the effect of RES on initiation and progression of EAE. These studies are aimed at providing insights into the efficacy of RES mainly in acute, remitting-relapsing and chronic forms of the disease which represent diverse pathological and immunological characteristics. Together, our studies should provide novel mechanistic clues on how RES helps in the treatment of MS and develop better CAM therapies to control the disease.

多发性硬化症（MS）是一种自身免疫性疾病，在美国影响约40万人。这是一辈子的事 主要在年轻人中诊断的慢性疾病。目前还没有治愈多发性硬化症的方法 包括使用经常表现出毒副作用的免疫抑制药物。因此， 寻找针对炎症细胞成分的替代和更有效的治疗策略。凸轮 治疗构成了治疗和控制该疾病的重要策略。实验性自身免疫性 脑脊髓炎是通过注射自身抗原，髓鞘碱性蛋白， 蛋白脂质蛋白或髓磷脂少突胶质细胞糖蛋白和佐剂。白藜芦醇（RES; 3，5，4 '- 三羟基二苯乙烯），一种非黄酮类多酚，存在于各种植物中，包括桑葚、花生和 葡萄已被证明具有有益的效果，特别是对心血管疾病，通过其 不动产。我们的初步研究表明，RES主要诱导细胞凋亡， 在活化的T细胞中通过Fas-FasL相互作用，涉及芳烃受体（AhR）和雌激素 受体（ER）。此外，在体内，RES下调CD 44和上调FoxpS。我们也很兴奋， 我们的发现是RES治疗减少了EAE的炎症和临床症状。在当前 在这项研究中，我们将通过多种途径来检验RES治疗对EAE有效的中心假设。 包括诱导髓鞘特异性T细胞凋亡、抑制DC功能、减少 CMS中的T细胞浸润是由于T细胞上的CD 44下调和T细胞的上调。我们将 具体目标：#1。Fas与FasL相互作用在白藜芦醇诱导细胞凋亡中的作用 在T细胞和树突状细胞（DC）中，涉及自分泌或旁分泌途径。2.调查AhR的作用 在T中RES诱导的Fas-FasL上调和随后的凋亡中cells.tf 3.测试ER在 RES治疗后诱导T细胞凋亡和外周T细胞功能障碍。4.探讨蛋白酶体抑制剂 RES对EAE的发生和进展的影响。这些研究的目的是提供洞察力的功效， RES主要表现为急性、缓解-复发和慢性等多种形式， 病理学和免疫学特征。总之，我们的研究应该提供新的机制， 关于RES如何帮助治疗MS和开发更好的CAM疗法以控制疾病的线索。