Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

摘要 最近在这个实验室获得的证据表明，减少核激活的治疗方法 在转录因子中，核因子-kappaB(NFkappaB)在大幅度降低 重度营养不良患者横纹肌纤维丢失与静息膜电位的恢复 肌纤维[2]。这些结果表明，显然有必要研究核因子？B的潜在临床应用。 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 确定柳氮磺胺吡啶抑制营养不良肌肉中核因子B途径的临床有效性。柳氮磺吡啶 尤其令人感兴趣，因为它目前在慢性基础上被用于治疗两种疾病的炎症性疾病 成人和儿童。本科生、研究生和博士研究生(A.T.斯蒂尔大学、杜鲁门州立大学) 将参与评估柳氮磺吡啶治疗对两个分离的MDX患者张力发展的影响 对完整的MDX小鼠的肌肉(腓肠肌、肋隔肌)和全身力量的影响。这项研究发表在 同时进行翻译研究，包括评估核因子？B的胞浆和核水平。 慢性处理MDX肌肉，静息状态下炎性细胞因子在血浆和肌肉提取液中的表达 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，纹状纤维与坏死性纤维的比例，着丝粒百分率，以及 营养不良的MDX肌纤维直径和横截面积。拟议的研究将测试具体的 柳氮磺胺吡啶治疗改善MDX小鼠肌肉功能的假说 可用于Duchenne和Becker肌肉患者临床试验的临床前信息 营养不良。项目叙事 这些研究将检验柳氮磺吡啶的潜在治疗效果，柳氮磺胺吡啶是一类 最近被证明对MDX小鼠有有益影响的药物(核因子B抑制剂)，这是一种模型 治疗杜氏肌营养不良症。柳氮磺胺吡啶目前用于治疗这两种疾病的炎症情况 儿童和成人，拟议的调查结果将为 柳氮磺胺吡啶治疗Duchenne和Becker的临床试验研究 肌肉营养不良症。

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.