Preclinical Trials of NFkappaB Inhibition in the Treatment of Muscular Dystrophy

抑制 NFkappaB 治疗肌营养不良症的临床前试验

• 批准号: 8408840
• 负责人: C George CARLSON
• 金额: $ 3.48万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8408840
• 关键词: Preclinical; Trials; NFkappaB; Inhibition; Treatment

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.

抽象的 该实验室最近获得的证据表明，减少核活化的治疗 转录因子核因子-κB (NF?B) 在显着减少 严重营养不良 (mdx) 患者横纹肌纤维的损失和静息膜电位的恢复 肌纤维[2]。这些结果表明显然需要研究 NF?B 的潜在临床效用 治疗杜氏肌营养不良症和贝克尔肌营养不良症的抑制剂。这些拟议研究的目的是 确定柳氮磺胺吡啶在营养不良性肌肉中抑制 NF?B 通路的临床效用。柳氮磺吡啶 特别令人感兴趣，因为它目前长期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 D.O.学生（A.T.斯蒂尔大学、杜鲁门州立大学） 将参与评估柳氮磺吡啶治疗对两个孤立的MDX紧张发展的影响 完整 mdx 小鼠的肌肉（腓肠肌、肋膈肌）和全身力量。这项研究是在 与翻译研究并行，包括评估 NF?B 的胞质和核水平 长期治疗的 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、横纹纤维与坏死纤维的比例、中心成核百分比以及分布 营养不良的 mdx 肌肉的纤维直径和横截面积。拟议的研究将测试具体的 假设柳氮磺胺吡啶治疗可改善 mdx 小鼠的肌肉功能，并提供必需的 可用于 Duchenne 和 Becker 肌病患者临床试验的临床前信息 营养不良。项目叙述 这些研究将检验柳氮磺吡啶的潜在治疗功效，柳氮磺吡啶是一类药物的成员。 最近被证明对 mdx 小鼠模型具有有益作用的药物（NF?B 抑制剂） 用于杜氏肌营养不良症。柳氮磺吡啶目前用于治疗两种疾病的炎症： 儿童和成人，拟议调查的结果将为 建立临床试验来测试柳氮磺吡啶治疗 Duchenne 和 Becker 患者的疗效 肌肉萎缩症。

项目成果

In vivo treatment with the NF-κB inhibitor ursodeoxycholic acid (UDCA) improves tension development in the isolated mdx costal diaphragm.

使用 NF-κB 抑制剂熊去氧胆酸 (UDCA) 进行体内治疗可改善离体 mdx 肋膈肌的张力发展。

• DOI: 10.1002/mus.24755
• 发表时间: 2016
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Carlson,CGeorge;Potter,Ross;Yu,Vivien;Luo,Kevin;Lavin,Jesse;Nielsen,Cory
• 通讯作者: Nielsen,Cory

The influence of passive stretch and NF-κB inhibitors on the morphology of dystrophic muscle fibers.

被动拉伸和NF-κB抑制剂对营养不良肌纤维形态的影响。

• DOI: 10.1002/ar.21294
• 发表时间: 2011-01
• 期刊: ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY
• 影响因子: 2
• 作者: Siegel, A. S.;Henley, S.;Zimmerman, A.;Miles, M.;Plummer, R.;Kurz, J.;Balch, F.;Rhodes, J. A.;Shinn, G. L.;Carlson, C. G.
• 通讯作者: Carlson, C. G.

Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF-κB-dependent negative modulation of ouabain sensitive Na+-K+ pump activity.

• DOI: 10.1016/j.jns.2011.01.015
• 发表时间: 2011-04-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Miles, M. T.;Cottey, E.;Cottey, A.;Stefanski, C.;Carlson, C. G.
• 通讯作者: Carlson, C. G.

Soluble activin receptor type IIB increases forward pulling tension in the mdx mouse.

可溶蛋白受体IIB型会增加MDX小鼠中的向前拉张力。

• DOI: 10.1002/mus.21944
• 发表时间: 2011-05
• 期刊: MUSCLE & NERVE
• 影响因子: 3.4
• 作者: Carlson, C. George;Bruemmer, Kay;Sesti, Jenna;Stefanski, Casey;Curtis, Heather;Ucran, Jeffrey;Lachey, Jennifer;Seehra, Jasbir S.
• 通讯作者: Seehra, Jasbir S.

Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-kappaB pathway.

• DOI: 10.1016/j.jns.2010.04.007
• 发表时间: 2010-07-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Graham, K. M.;Singh, R.;Millman, G.;Malnassy, G.;Gatti, F.;Bruemmer, K.;Stefanski, C.;Curtis, H.;Sesti, J.;Carlson, C. G.
• 通讯作者: Carlson, C. G.