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: 2579544
• 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/2579544
• 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 that processes up to 200 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-I or HIV and HTLV-I-infected lymphoid cells to infect human myotubes in culture and induce expression of new surface antigens; c) study the expression of the poliovirus receptor in human muscle in vivo and in vitro, the ability of the poliovirus to infect and replicate in human myotubes and the mechanism of apoptotic cell death induced by the poliovirus; (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) use animal models to study: (i) the pathogenesis of retrovirus-induced inflammatory myopathy by examining muscles from monkeys infected with the simian immunodeficiency virus; (ii) 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; (iii) the effect of L-carnitine in reversing or improving the AZT-induced myopathy in the rats; and (iv) the mechanism by which dideoxycytidine induces neuro~toxicity in healthy rats.

该科负责肌肉酶组织化学实验室， 每年进行多达200次肌肉和神经活检，以诊断和 研究性研究。检查的肌肉来自患有神经肌肉疾病的患者 与全身、自身免疫、病毒、代谢、 内分泌或感染性疾病；原发性神经肌肉疾病，如 多发性肌炎、皮肌炎、神经源性肌肉萎缩、肌肉 营养不良、脊髓灰质炎后综合征、多发性神经病、线粒体 脑肌病；以及生化和遗传性肌肉疾病患者 疾病，如中枢核心病或肥厚性心肌病。 该实验室还参与了以下免疫学研究， 生物化学和病毒学研究，以检查易感性 肌肉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及其成熟度 通过检测卫星细胞对神经细胞黏附的表达 分子和层粘连蛋白；(B)研究肌肉和神经的敏感性 对逆转录病毒的感染和HIV和HTLV-I或HIV的能力 和HTLV-I感染的淋巴样细胞在培养中感染人肌管 并诱导新的表面抗原的表达；c)研究表达 在活体和体外人体肌肉中脊髓灰质炎病毒受体的研究 脊髓灰质炎病毒在人肌管中感染和复制的能力 脊髓灰质炎病毒导致细胞凋亡的机制；(D) 细胞因子和淋巴因子对人肌管和肌细胞的影响 体外检查静脉注射免疫球蛋白等潜在的治疗剂是否可以 抑制其毒性或免疫增强作用；(E)审查其作用 细胞间黏附分子-I在体内外促进肌细胞毒作用中的作用 细胞毒性T细胞与肌管的黏附；(F)研究 AZT对肌肉线粒体、线粒体氧化磷酸化和 将AZT应用于人肌肉培养中的线粒体DNA；(G)研究 L-卡尼汀逆转线粒体异常的作用 AZT在体外对人肌管的诱导作用；及(H)利用动物模型 研究：(I)逆转录病毒诱导的炎症性肌病的发病机制 通过检查感染了猴的猴子的肌肉 免疫缺陷病毒；(II)AZT诱导线粒体的机制 肌病的结构、代谢和功能检查 注射AZT的健康大鼠肌肉线粒体的变化； (3)L-卡尼汀逆转或改善AZT的作用 大鼠的肌病；以及(Iv)双脱氧胞苷的作用机制 对健康大鼠产生神经毒性。