DWORF在大型杜氏肌营养不良动物模型中表达降低。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-06-01 Epub Date: 2025-06-25 DOI:10.1242/dmm.052285
Aaron M Gibson, Xiufang Pan, Omar Brito-Estrada, James A Teixeira, Lauren K Carl, Yongping Yue, Michael L Kamradt, Matthew J Burke, Caris A Wadding-Lee, Gang Yao, Roland W Herzog, Dongsheng Duan, Catherine A Makarewich
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引用次数: 0

摘要

杜氏肌营养不良症(DMD)是一种由细胞质钙超载引起的致死性肌肉萎缩疾病,可导致肌肉变性。Sarco/内质网钙atp酶(SERCA)是胞质钙水平的关键调节因子,在DMD动物模型和人类患者中表现出活性降低。侏儒开放阅读框(DWORF)是一种SERCA阳性调节因子,在mdx DMD小鼠中下调,腺相关病毒介导的DWORF过表达已被证明可以改善DMD心肌病。犬类DMD模型为将小鼠的发现转化为人类提供了一个重要的桥梁。为了研究DWORF在该模型中的表达,由于现有的小鼠抗体无效,我们开发了一种犬特异性抗DWORF抗体。该抗体在人、猪、猫和兔肌肉中检测到DWORF,而在小鼠肌肉中检测不到。DWORF在新生正常犬的肌肉组织中不存在,而在成年犬的肌肉组织中高表达。在8个月或更大的dmd影响犬中,DWORF在心脏和骨骼肌中的表达均显著降低。本研究为在犬DMD模型中评估基于dworf的基因治疗奠定了基础,提高了临床转化的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
DWORF expression is reduced in a large animal model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease driven by cytosolic calcium overload, which leads to muscle degeneration. Sarco/endoplasmic reticulum calcium ATPase (SERCA), a key regulator of cytosolic calcium levels, exhibits reduced activity in animal models of DMD and human patients. Dwarf open reading frame (DWORF), a positive SERCA regulator, is downregulated in mdx DMD mice, and adeno-associated virus-mediated DWORF overexpression has been shown to ameliorate DMD cardiomyopathy. The canine DMD model provides a crucial bridge for translating findings from mice to humans. To investigate DWORF expression in this model, we developed a canine-specific anti-DWORF antibody, as the existing murine antibody is ineffective. This antibody detected DWORF in human, pig, cat and rabbit muscle, but not in mouse muscle. DWORF was absent in muscle tissues of neonatal normal dogs but highly expressed in those of adult dogs. In DMD-affected dogs aged 8 months or older, DWORF expression was significantly reduced in both cardiac and skeletal muscle. This study establishes a foundation for evaluating DWORF-based gene therapy in the canine DMD model, advancing the potential for clinical translation.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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