COMBINED CLINICAL, VIRAL AND IMMUNOLOGICAL STUDIES IN NEUROMUSCULAR DISEASES

神经肌肉疾病的临床、病毒和免疫学综合研究

• 批准号: 6290611
• 负责人: Marinos Dalakas
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290611
• 关键词: HIV infections; amyotrophic lateral sclerosis; carbonic anhydrase inhibitors; carnitine; clinical research; clinical trials; dermatomyositis; human subject; human therapy evaluation; hypokalemia; immunity; immunocytochemistry; immunoglobulins; immunotherapy; longitudinal human study; muscular dystrophy; myelinopathy; neuromuscular disorder; neuromuscular disorder chemotherapy; paralysis; pathologic process; poliomyelitis; polymerase chain reaction; polymyositis; zidovudine

Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis, dermatomyositis, inclusion body myositis, motor neuron diseases including post-polio syndrome, demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, metabolic myopathies, hypokalemic periodic paralysis, certain dystrophies, myasthenia gravis, diabetic neuropathies and stiff-man syndrome. Persistent or mutant poliovirus is sought in patients with post-polio syndrome and ALS. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is examined by analysis of the neuroendocrine axis, magnetic resonance spectroscopy and sleep studies. In inflammatory myopathies, the role of cytokines TGF-beta and IL-1 and metalloproteins MMP-2 and MMP-9 in promoting amyloid formation and persistent endomysial inflammation were studied. The antigenic specificity and in situ clonal expansion of the endomysial T cells of patients with inflammatory myopathies and neuropathies was studied by examining the T cell receptor profile and sequencing the CD3 region. The capacity of the muscle fiber or the Schwann cell to behave as antigen-present cells and bind to their ligands, CTLA-4 and CD28, on T cells was examined. The lack of apoptosis in muscle and T cells was explored by studying IAP-like proteins and mRNA expression. The mechanism by which anti-retroviral nucleoside analogs cause mitochondrial dysfunction and mDNA deletion in muscle and nerve was investigated. The cytotoxic basis of anti-GAD antibodies in patients with stiff-man syndrome was investigated and changes in the antibody titers were studied in vivo and in vitro as well as during therapy. The role of amphiphysin and GAD in this disease, as well as other autoimmune disorders affecting synaptic transmission, are being explored. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were discovered in the same patients. The functional role of these mutations was studied in transfected cell lines. The type of glucolipids recognized as antigens by certain IgM-associated paraproteinemic neuropathies was also examined.Randomized-controlled clinical trials are being conducted with high-dose intravenous immunoglobulin in patients with polymyositis, dermatomyositis, inclusion body myositis, chronic inflammatory and paraproteinemic demyelinating polyneuropathies, and stiff-man syndrome. A similar study in diabetic proximal autoimmune neuropathy will soon begin. Experimentally, the suppression of the endomysial inflammatory response in TGF-beta double knock-out mice was studied using fibronectin peptide motifs as experimental therapies. - Myopathies, Neuropathies, Motor neuron diseases, Immunology, Virology and toxicology of muscle and nerve, Immunotherapies - Human Subjects

临床和实验室研究是为了确定神经肌肉系统各种疾病的病因(感染、免疫和/或遗传学)并设计有效的治疗方法。目前的研究涉及多发性肌炎、皮肌炎、包涵体肌炎、运动神经元疾病(包括脊髓灰质炎后综合征)、脱髓鞘多神经病、与艾滋病毒感染相关的神经肌肉疾病、代谢性肌病、低钾周期性瘫痪、某些营养不良、重症肌无力、糖尿病神经病变和僵硬综合征。在脊髓灰质炎后综合征和肌萎缩侧索硬化症患者中寻找持续或突变的脊髓灰质炎病毒。脊髓灰质炎后疲劳是许多患者常见的致残症状，通过对神经内分泌轴的分析、磁共振波谱和睡眠研究，对其机制进行了研究。在炎症性肌病中，研究了细胞因子转化生长因子-β和白介素1以及金属蛋白基质金属蛋白酶-2和基质金属蛋白酶-9在促进淀粉样蛋白形成和持续性内膜炎症中的作用。对炎症性肌病和神经病患者肌内T细胞的抗原特异性和原位克隆性扩增进行了检测和CD3区序列测定。检测了肌肉纤维或雪旺细胞作为抗原呈递细胞并与其T细胞上的配体CTLA-4和CD28结合的能力。通过研究IAP样蛋白和mRNA的表达，探讨了肌肉和T细胞缺乏凋亡的原因。研究了抗逆转录病毒核苷类似物导致肌肉和神经线粒体功能障碍和mDNA缺失的机制。本文探讨了僵人综合征患者抗GAD抗体的细胞毒理基础，并观察了体内、体外和治疗过程中抗体效价的变化。两栖动物和GAD在这种疾病以及其他影响突触传递的自身免疫性疾病中的作用正在探索中。研究了与心肌病相关的远端肌病的原因，并在相同的患者中发现了结蛋白基因的突变。研究了这些突变在转基因细胞系中的功能作用。对某些与IgM相关的副蛋白血症神经病变识别为抗原的糖脂类型也进行了检查。大剂量静脉注射免疫球蛋白正在多发性肌炎、皮肌炎、包涵体肌炎、慢性炎症性和副蛋白血症脱髓鞘多神经病和僵人综合征患者中进行随机对照临床试验。一项针对糖尿病近端自身免疫性神经病变的类似研究即将开始。实验方面，以纤维连接蛋白多肽为实验药物，研究了其对转化生长因子-β双基因敲除小鼠内膜炎症反应的抑制作用。-肌肉疾病、神经疾病、运动神经元疾病、免疫学、肌肉和神经的病毒学和毒理学、免疫疗法-人类受试者