在DMD基因敲除斑马鱼和患者源性成肌细胞培养中,Jagged1影响下病理参数的缓解

IF 1.5 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

摘要

杜氏肌营养不良症(DMD)是一种主要影响男性儿童的x连锁退行性疾病,伴有全身骨骼肌和心脏的进行性无力。到青少年晚期,逐渐丧失行走能力、心脏无力和呼吸能力。心脏或肺功能障碍导致患者在第二个或第三个十年早期死亡。类固醇治疗延缓疾病进展2-3年,尽管有严重的副作用。fda批准的少数基因疗法是针对突变的,而且价格过高。患有DMD的儿童的医疗需求尚未得到满足。有趣的是,之前的一项研究表明,单核苷酸变化导致Jagged1过表达,从而避免了1-1.5岁严重肌肉萎缩症的金毛猎犬的早期死亡和活动能力丧失。确定Jagged1过表达减轻的病理过程可能有助于理解这种拯救的机制。因此,我们在斑马鱼中产生了DMD敲除,斑马鱼是另一种严重的DMD模型,人类Jagged1 (JAG1)过表达。病理方面如细胞死亡、细胞增殖、细胞质和线粒体氧化应激在营养不良组、抢救组和对照组之间进行比较。令人惊讶的是,JAG1在抢救过程中增加了线粒体氧化应激,同时减少了其他病理过程。同样,在体外分化的患者源性肌管中,Jag1肽治疗也增加了线粒体ROS的产生,这表明一种保守的机制参与了挽救。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mitigation of pathological parameters under Jagged1 influence in DMD knockout zebrafish and patient-derived myoblast cultures
Duchenne muscular dystrophy (DMD) is an X-linked, degenerative disease mainly affecting male children, with progressive weakness of whole-body skeletal muscles and the heart. There is a gradual loss of ambulation, heart weakness, and breathing capacity by late teens. Heart or lung dysfunction causes early death in patients during the second or third decade. Steroid treatment delays disease progression by 2-3 years, albeit with serious side effects. The few FDA-approved gene therapies are mutation-specific and exorbitantly priced. There is an unmet medical need for the children affected with DMD. Interestingly, a previous study showed that single nucleotide change caused Jagged1 overexpression, which resulted in avoidance of early death and ambulatory loss in 1-1.5-year-old golden retriever dogs severely affected with muscular dystrophy. Identifying the pathological processes mitigated by Jagged1 overexpression might help understand the mechanism of this rescue. Hence, we generated DMD knockout in zebrafish, another severe model of DMD with overexpression of the human Jagged1 (JAG1). Pathological aspects like cell death, cell proliferation, cytoplasmic and mitochondrial oxidative stress were compared between dystrophic, rescued, and control groups. Surprisingly, JAG1 increased mitochondrial oxidative stress during rescue, while reducing other pathological processes. Similarly, increased mitochondrial ROS production occurred with Jag1 peptide treatment in in vitro differentiated patient-derived myotubes, suggesting a conserved mechanism involved in the rescue.
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来源期刊
Indian journal of biochemistry & biophysics
Indian journal of biochemistry & biophysics 生物-生化与分子生物学
CiteScore
2.90
自引率
50.00%
发文量
88
审稿时长
3 months
期刊介绍: Started in 1964, this journal publishes original research articles in the following areas: structure-function relationships of biomolecules; biomolecular recognition, protein-protein and protein-DNA interactions; gene-cloning, genetic engineering, genome analysis, gene targeting, gene expression, vectors, gene therapy; drug targeting, drug design; molecular basis of genetic diseases; conformational studies, computer simulation, novel DNA structures and their biological implications, protein folding; enzymes structure, catalytic mechanisms, regulation; membrane biochemistry, transport, ion channels, signal transduction, cell-cell communication, glycobiology; receptors, antigen-antibody binding, neurochemistry, ageing, apoptosis, cell cycle control; hormones, growth factors; oncogenes, host-virus interactions, viral assembly and structure; intermediary metabolism, molecular basis of disease processes, vitamins, coenzymes, carrier proteins, toxicology; plant and microbial biochemistry; surface forces, micelles and microemulsions, colloids, electrical phenomena, etc. in biological systems. Solicited peer reviewed articles on contemporary Themes and Methods in Biochemistry and Biophysics form an important feature of IJBB. Review articles on a current topic in the above fields are also considered. They must dwell more on research work done during the last couple of years in the field and authors should integrate their own work with that of others with acumen and authenticity, mere compilation of references by a third party is discouraged. While IJBB strongly promotes innovative novel research works for publication as full length papers, it also considers research data emanating from limited objectives, and extension of ongoing experimental works as ‘Notes’. IJBB follows “Double Blind Review process” where author names, affiliations and other correspondence details are removed to ensure fare evaluation. At the same time, reviewer names are not disclosed to authors.
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