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: 6111839
• 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/6111839
• 关键词: HIV infections; autoimmune disorder; carnitine; central nervous system; clinical research; dermatomyositis; disease /disorder model; drug adverse effect; histocompatibility antigens; human immunodeficiency virus; human subject; immunopathology diagnosis; inborn metabolism disorder; laboratory mouse; laboratory rat; mitochondria; molecular pathology; muscular dystrophy; myocardium disorder; nervous system disorder; nervous system disorder diagnosis; neural cell adhesion molecules; neuromuscular disorder; poliomyelitis; polymyositis; simian immunodeficiency virus; virus receptors; zidovudine

The Section processes more than 100 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, inclusion body myositis, neurogenic muscular atrophies, muscular dystrophies, post-polio syndrome, polyneuropathies, mitochondrial encephalomyopathies; patients with biochemical and genetic muscle diseases, such as phosphofructokinase deficiency, hypertrophic cardiomyopathy; or storage myopathies; and from experimental animals. 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 genetic defect in patients with various metabolic myopathies (with emphasis on phosphofructokinase deficiency), mitochondriopathies and hereditary vacuolar myopathies with emphasis on desmin-storage; (b) study the binding of immunoglobulin from patients with paraproteinemic neuropathies to human glucolipids and glucoproteins and correlate the immunoreactivity with the clinical picture; (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 (apoptosis or necrosis) by which the poliovirus kills motor neurons; (d) study the effect of cytokines and lymphokines with emphasis on IL1, IL2, TGFbeta on human myotubes and examine in vitro if various immunotherapeutic agents can inhibit their toxic or immunopotentiating effect; (e) study the up-regulation of pro-apoptotic or anti-apoptotic molecules such as fas, fasL, Bcl-2, Bcl-XL, FLIP, human ILP in human muscle in vitro and in vivo; (f) study surface molecules, their mRNA and ligands involved in antigen presentation in the muscle biopsy specimens from patients with autoimmune disorders; g) examine the expression of matrix metalloproteinases using immunocytochemistry, zymography and PCR in the tissues of patients with autoimmune neuropathies and myopathies; h) study the toxicity of nucleoside analogues, such as AZT and FIAU to muscle mitochondria, mitochondrial oxidative phosphorylation and mit. DNA by applying these agents to human muscle in culture. Examination of selective, single fiber, mDNA depletion is considered; i) use animal models to study: (i) the mechanism of AZT-induced mitochondrial myopathy and ddC-induced neurotoxicity by examining the structural, metabolic and functional alterations in the muscle and nerve mitochondria of healthy rats injected with AZT or ddC; (ii) the inflammatory response in TGF-beta double knock-out mice and the role of various integrins; and (iii) the T cell receptor and cytokine profile in mdx mice treated with an adenovirus vector carrying the dystrophin gene.

该科处理100多块肌肉， 神经活检用于诊断和研究。 检查的肌肉来自以下患者：神经肌肉 与全身性、自身免疫性、病毒性、代谢性、 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、包涵体肌炎 神经源性肌萎缩，肌营养不良，脊髓灰质炎后 综合征、多发性神经病、线粒体脑肌病; 患有生化和遗传性肌肉疾病的患者，如 磷酸果糖激酶缺乏、肥厚性心肌病;或 储存性肌病;和来自实验动物。实验室 还涉及以下免疫学、生物化学和 病毒学研究，检查肌肉的易感性， 神经免疫或病毒介导的损伤：（a）研究遗传 各种代谢性肌病患者的缺陷（强调 磷酸果糖激酶缺乏症）、糖尿病和 遗传性空泡性肌病，强调结蛋白储存; (b)研究免疫球蛋白的结合， 对人类糖脂的副蛋白血症性神经病， 并将免疫反应性与临床 （c）研究小儿麻痹病毒受体在人体内的表现 在体内和体外的肌肉中，脊髓灰质炎病毒感染和 复制在人类肌管和机制（细胞凋亡或 （d）研究脊髓灰质炎病毒杀死运动神经元的机制， 细胞因子和淋巴因子的作用，重点是IL 1，IL 2， TGF β在人肌管上的表达，并在体外检查是否存在各种 免疫抑制剂可以抑制它们的毒性或 免疫增强作用;（e）研究 促凋亡或抗凋亡分子如Fas，fasL，Bcl-2， 体外和体内人肌肉中的Bcl-XL、FLIP、人ILP;（f） 研究表面分子，它们的mRNA和配体参与 患者肌肉活检标本中的抗原呈递 自身免疫性疾病; g）检查基质的表达 金属蛋白酶，使用免疫细胞化学，酶谱和 自身免疫性神经病患者组织中的PCR， h）研究核苷类似物的毒性，例如 AZT和FIAU对肌肉线粒体，线粒体氧化 磷酸化和MIT。将这些试剂应用于人类 肌肉文化选择性、单纤维、mDNA检查 考虑消耗; i）使用动物模型研究：（i） AZT诱导的线粒体肌病的机制和 ddC诱导的神经毒性，通过检查结构，代谢 以及肌肉和神经线粒体的功能改变 注射AZT或ddC的健康大鼠;（ii）炎症 TGF-β双基因敲除小鼠中的反应以及 各种整联蛋白;和（iii）T细胞受体和细胞因子谱， 用携带肌营养不良蛋白的腺病毒载体处理的mdx小鼠 基因