Expression profiling of disease progression in canine model of Duchenne muscular dystrophy.
Expression profiling of disease progression in canine model of Duchenne muscular dystrophy.
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DOI：
10.1371/journal.pone.0194485
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Kornegay JN
中科院分区：
文献类型：
--
作者：
Brinkmeyer-Langford C;Chu C;Balog-Alvarez C;Yu X;Cai JJ;Nabity M;Kornegay JN
杜氏肌营养不良症（DMD）由于缺乏功能性肌营养不良蛋白，每5,000名男孩中就有1名患有进行性残疾。尽管对DMD疾病表现和进展的认识有了很大的进步-部分归因于使用疾病的小鼠和犬模型的研究-目前的DMD治疗对所有患者都不同样有效。因此，仍然需要转化动物模型，其中可以鉴定和评估新的治疗靶点。金毛寻回犬肌营养不良症（GRMD）是一种表型和遗传上同源的DMD动物模型。与DMD一样，GRMD的疾病进展速度差异很大。然而，与DMD不同的是，所有GRMD犬都具有相同的因果突变;因此，表型变异的遗传修饰剂相对更容易识别。此外，本研究中使用的GRMD犬居住在同一群体中，减少了环境对表型变异的混杂影响。为了检测疾病进展的调节剂，我们使用RNA测序为9只狗开发了基因表达谱：6只GRMD狗（3只疾病进展较快，3只疾病进展较慢，基于定量客观生物标志物）和3只来自同一群体的对照狗。在2个时间点对所有犬进行评价：早期疾病发作（3月龄）和GRMD稳定的时间点（6月龄），使用定量、客观生物标志物进行评价，该生物标志物被鉴定为对相关性/近亲繁殖的影响具有鲁棒性。在所有比较中，差异表达最多的基因分为3类：肌生成/肌肉再生、代谢和炎症。我们的研究结果在很大程度上与DMD和小鼠模型研究一致，加强了GRMD作为转化模型的实用性。新的发现包括在进展较快的GRMD犬中几丁质酶3样1（CHI 3L 1）的强烈上调，这表明以前未探索的机制是GRMD和DMD进展速度的基础。总之，我们的研究结果支持RNA测序用于评估GRMD进展速度的潜在生物标志物的效用，并且对于确定DMD研究的新探索途径是有价值的。
Duchenne muscular dystrophy (DMD) causes progressive disability in 1 of every 5,000 boys due to the lack of functional dystrophin protein. Despite much advancement in knowledge about DMD disease presentation and progression—attributable in part to studies using mouse and canine models of the disease–current DMD treatments are not equally effective in all patients. There remains, therefore, a need for translational animal models in which novel treatment targets can be identified and evaluated. Golden Retriever muscular dystrophy (GRMD) is a phenotypically and genetically homologous animal model of DMD. As with DMD, speed of disease progression in GRMD varies substantially. However, unlike DMD, all GRMD dogs possess the same causal mutation; therefore genetic modifiers of phenotypic variation are relatively easier to identify. Furthermore, the GRMD dogs used in this study reside within the same colony, reducing the confounding effects of environment on phenotypic variation. To detect modifiers of disease progression, we developed gene expression profiles using RNA sequencing for 9 dogs: 6 GRMD dogs (3 with faster-progressing and 3 with slower-progressing disease, based on quantitative, objective biomarkers) and 3 control dogs from the same colony. All dogs were evaluated at 2 time points: early disease onset (3 months of age) and the point at which GRMD stabilizes (6 months of age) using quantitative, objective biomarkers identified as robust against the effects of relatedness/inbreeding. Across all comparisons, the most differentially expressed genes fell into 3 categories: myogenesis/muscle regeneration, metabolism, and inflammation. Our findings are largely in concordance with DMD and mouse model studies, reinforcing the utility of GRMD as a translational model. Novel findings include the strong up-regulation of chitinase 3-like 1 (CHI3L1) in faster-progressing GRMD dogs, suggesting previously unexplored mechanisms underlie progression speed in GRMD and DMD. In summary, our findings support the utility of RNA sequencing for evaluating potential biomarkers of GRMD progression speed, and are valuable for identifying new avenues of exploration in DMD research.
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影响因子：
3.4
作者：
Comim, Clarissa M.;Hoepers, Andreza;Quevedo, Joao
通讯作者：
Quevedo, Joao
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
2.8
作者：
Bakay, M;Zhao, P;Hoffman, EP
通讯作者：
Hoffman, EP
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y