Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

摘要 本实验室获得的最新证据表明，减少核活化的处理 转录因子核因子-κ B（NF？B）在显著降低 严重营养不良（mdx）患者横纹肌纤维的丢失和静息膜电位的恢复 肌纤维[2]。这些结果表明，一个明确的需要调查潜在的临床应用NF？B 治疗Duchenne和Becker肌营养不良症的抑制剂。这些拟议研究的目的是 确定柳氮磺胺吡啶的临床效用，抑制NF？营养不良肌肉中的B通路。磺胺吡啶 是特别令人感兴趣的，因为它目前在慢性基础上用于治疗 成人和儿童。本科生，研究生，和D. O。学生（A.T.斯蒂尔大学、杜鲁门州立大学） 将参与评估柳氮磺胺吡啶治疗对两个孤立mdx中紧张发展的影响。 肌肉（腓肠肌、肋膈）和完整mdx小鼠的全身力量。这项研究是在 与翻译调查，包括评估细胞溶质和核水平的NF？B in 长期处理mdx肌肉，血浆和肌肉提取物中炎性细胞因子的表达，静息 膜电位、血浆肌酸激酶水平、骨骼肌纤维化和组织学测定。 纤维总数、条纹纤维与坏死纤维的比例、中央核形成百分比以及 纤维直径和横截面积在营养不良的mdx肌肉。拟议的研究将测试具体的 假设柳氮磺胺吡啶治疗改善了mdx小鼠的肌肉功能， 可用于Duchenne和Becker肌营养不良患者临床试验的临床前信息 营养不良项目叙述 这些研究将检查柳氮磺胺吡啶的潜在治疗效果，柳氮磺胺吡啶是一类 药物（NF？B抑制剂），这些药物最近在mdx小鼠模型中显示出有益的效果， 治疗杜氏肌营养不良症柳氮磺胺吡啶目前用于治疗炎症条件， 儿童和成人，拟议调查的结果将提供关键信息， 建立临床试验，以测试柳氮磺胺吡啶治疗杜氏和贝克尔病患者的疗效 肌肉萎缩症

ABSTRACT Recent evidence obtained in this laboratory indicates that treatments which reduce the nuclear activation of the transcription factor nuclear factor-kappaB (NF?B) have distinct beneficial effects in substantially reducing the loss of striated muscle fibers and restoring the resting membrane potential in severely dystrophic (mdx) muscle fibers [2]. These results indicate a clear need for investigating the potential clinical utility of NF?B inhibitors in treating Duchenne and Becker muscular dystrophies. The purpose of these proposed studies is to determine the clinical utility of sulfasalazine which inhibits the NF?B pathway in dystrophic muscle. Sulfasalazine is of particular interest because it is currently used on a chronic basis to treat inflammatory disorders in both adults and children. Undergraduate, graduate, and D.O. students (A.T. Still University, Truman State University) will be involved in assessing the effects of sulfasalazine treatment on tension development in two isolated mdx muscles (gastrocnemius, costal diaphragm) and on whole body strength in intact mdx mice. This study is done in parallel with translational investigations that include assessments of cytosolic and nuclear levels of NF?B in chronically treated mdx muscle, the expression of inflammatory cytokines in plasma and muscle extracts, resting membrane potential, plasma creatine kinase levels, skeletal muscle fibrosis, and histological determinations of the total number of fibers, the proportion of striated vs necrotic fibers, percent centronucleation, and the distribution of fiber diameter and cross sectional areas in dystrophic mdx muscle. The proposed studies will test the specific hypothesis that sulfasalazine treatment improves muscle function in the mdx mouse and will provide essential pre-clinical information that can be used in clinical trials for patients with Duchenne and Becker muscular dystrophies. PROJECT NARRATIVE These studies will examine the potential therapeutic efficacy of sulfasalazine which is a member of a class of drugs (NF?B inhibitors) that have recently been shown to have beneficial effects in the mdx mouse, a model for Duchenne muscular dystrophy. Sulfasalazine is currently used to treat inflammatory conditions in both children and adults, and the results of the proposed investigations will provide critical information for establishing clinical trials to test the efficacy of sulfasalazine in treating patients with Duchenne and Becker muscular dystrophy.