NEUROMUSCULAR AND CNS DISEASES AND THEIR EXPERIMENTAL MODELS

神经肌肉和中枢神经系统疾病及其实验模型

• 批准号: 3760251
• 负责人: M C 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/3760251
• 关键词: HIV infections; Primates; Retroviridae; autoimmune disorder; carnitine; central nervous system; dermatomyositis; disease /disorder model; drug adverse effect; histocompatibility antigens; human immunodeficiency virus; human subject; immunopathology diagnosis; laboratory rat; muscular dystrophy; myelinopathy; nervous system disorder; nervous system disorder diagnosis; neural cell adhesion molecules; neuromuscular disorder; poliomyelitis; polymyositis; simian immunodeficiency virus; virus receptors; zidovudine

The Section runs the Laboratory of Muscle Enzyme Histochemistry than processes up to 300 muscle and nerve biopsies per year for diagnostic and research studies. Examined muscles are from patients with: neuromuscular manifestations related to systemic, autoimmune, viral, metabolic, endocrine or infectious diseases; primary neuromuscular disorders, such as polymyositis, dermatomyositis, neurogenic muscular atrophies, muscular dystrophies, post-polio syndrome, polyneuropathies, mitochondrial encephalomyopathies; and patients with biochemical and genetic muscle diseases, such as central core disease or hypertrophic cardiomyopathy. The Laboratory is also involved in the following immunological, biochemical and virological studies that examine the susceptibility of the muscle and nerve to immune or viral mediated injuries: (a) Study the regeneration of human muscle in health and disease and the maturation of satellite cells by examining the expression of neural cell adhesion molecules and laminins; (b) study the susceptibility of muscle and nerve to infection with retroviruses and the ability of HIV and HTLV-l or HIV and HTLV-l-infected lymphoid cells to infect human myotubes in culture and induce expression of MHC- antigens; (c) study the expression of the poliovirus receptor in human muscle in vivo and in vitro, and the ability of the poliovirus to infect and replicate in human myotubes; (d) study the effect of cytokines and lymphokines on human myotubes and examine in vitro if potentially therapeutic agents such as IVIg can inhibit their toxic or immunopotentiating effect; (e) examine the role of ICAM-I in enhancing myocytotoxicity in vivo and in vitro by promoting the adhesion of cytotoxic T cells to myotubes; (f) study the toxicity of AZT to muscle mitochondria, mitochondrial oxidative phosphorylation and mitochondrial DNA by applying AZT to human muscle in culture; (g) study the effect of L-carnitine in reversing the mitochondrial abnormalities induced by AZT on human myotubes in vitro; and (h) using animal models. These models will be employed to study: (1) the pathogenesis of retrovirus-induced inflammatory myopathy by examining muscles from monkeys infected with the simian immunodeficiency virus; (2) the mechanism of AZT-induced mitochondrial myopathy by examining the structural, metabolic and functional alterations in the muscle mitochondria of healthy rats injected with AZT; (3) the effect of L-carnitine in reversing or improving the AZT-induced myopathy in the rats; and (4) the mechanism by which dideoxycytidine induces neurotoxicity in healthy rats.

该科负责肌肉酶组织化学实验室 每年处理多达 300 个肌肉和神经活检 诊断和研究。检查的肌肉来自患者 与：与全身、自身免疫相关的神经肌肉表现， 病毒、代谢、内分泌或传染病；基本的 神经肌肉疾病，例如多发性肌炎、皮肌炎、 神经源性肌肉萎缩症、肌营养不良症、脊髓灰质炎后 综合征，多发性神经病，线粒体脑肌病；和 患有生化和遗传性肌肉疾病的患者，例如 中央核心疾病或肥厚性心肌病。实验室 还涉及以下免疫学、生化和 检查肌肉敏感性的病毒学研究 和神经对免疫或病毒介导的损伤：(a) 研究 人体肌肉在健康和疾病中的再生以及 通过检查神经细胞的表达来观察卫星细胞的成熟 细胞粘附分子和层粘连蛋白； (b) 研究敏感性 肌肉和神经感染逆转录病毒的能力 HIV 和 HTLV-1 或 HIV 和 HTLV-1 感染的淋巴细胞 感染培养物中的人类肌管并诱导 MHC- 的表达 抗原； (c) 研究脊髓灰质炎病毒受体的表达 人体肌肉的体内和体外，以及 脊髓灰质炎病毒感染人类肌管并在其中复制； (d) 研究 细胞因子和淋巴因子对人体肌管的影响并检查 如果潜在的治疗药物如 IVIg 可以抑制体外 它们的毒性或免疫增强作用； (e) 审查的作用 ICAM-I 通过增强体内和体外肌细胞毒性 促进细胞毒性 T 细胞与肌管的粘附； (f) 研究 AZT 对肌肉线粒体、线粒体氧化的毒性 通过将 AZT 应用于人类来磷酸化和线粒体 DNA 文化中的肌肉； (g) 研究左旋肉碱的逆转作用 AZT 诱导的人肌管线粒体异常 体外； (h) 使用动物模型。这些模型将被采用 研究：（1）逆转录病毒引起的炎症的发病机制 通过检查感染猿猴的猴子的肌肉来发现肌病 免疫缺陷病毒； (2)AZT诱导的机制 通过检查线粒体肌病的结构、代谢和 健康大鼠肌肉线粒体的功能改变 注射AZT； (3)左旋肉碱的逆转或逆转作用 改善AZT所致大鼠肌病；和（4） 双脱氧胞苷诱导健康神经毒性的机制 老鼠。