Global gene expression profiling in R155H knock-in murine model of VCP disease.
Global gene expression profiling in R155H knock-in murine model of VCP disease.
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DOI：
10.1111/cts.12241
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发表时间：
2015-02
期刊：
影响因子：
--
通讯作者：
Kimonis VE
中科院分区：
文献类型：
--
作者：
Nalbandian A;Ghimbovschi S;Wang Z;Knoblach S;Llewellyn KJ;Vesa J;Hoffman EP;Kimonis VE
valosin containing protein （VCP）基因的显性突变导致包体肌病与骨Paget病和额颞叶痴呆（IBMPFD）相关，其特征是进行性肌肉无力、骨重塑功能障碍和额颞叶痴呆。最近，VCP与2%的家族性肌萎缩侧索硬化症（ALS）病例有关。VCP在多种细胞功能中发挥重要作用，包括膜融合、转录激活、核膜重建、有丝分裂后细胞器重组、细胞周期控制。为了阐明VCP疾病进展的病理机制，我们之前建立了带有R155H突变的VCPR155H/+小鼠模型。突变肌肉的组织学分析显示肌原纤维空泡化，位于中心的细胞核和肌肉纤维紊乱。DAVID利用基因注释对VCPR155H/+小鼠进行全局表达谱分析，确定了关键的失调信号通路，包括参与生理系统发育和功能、疾病和失调以及分子和细胞功能的基因。共有212个基因显著失调，其中一些基因参与了蛋白酶体功能和NF-κB信号级联的调节。通过使用定量逆转录酶聚合酶链式反应分析来测试参与各种信号级联反应的基因，验证了基因表达研究的结果。这项研究揭示了VCPR155H/+小鼠模型在理解引起vcp相关神经退行性疾病的细胞和分子机制以及发现患有这些衰弱性疾病的患者的新治疗进展和策略中的重要性。
Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), which is characterized by progressive muscle weakness, dysfunction in bone remodeling, and frontotemporal dementia. More recently, VCP has been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP plays a significant role in a plethora of cellular functions including membrane fusion, transcription activation, nuclear envelope reconstruction, post-mitotic organelle reassembly, cell cycle control. To elucidate the pathological mechanisms underlying the VCP disease progression, we have previously generated a VCPR155H/+ mouse model with the R155H mutation. Histological analyses of mutant muscle showed vacuolization of myofibrils, centrally located nuclei, and disorganized muscle fibers. Global expression profiling of VCPR155H/+ mice using gene annotations by DAVID identified key dysregulated signaling pathways including genes involved in the physiological system development and function, diseases and disorders, and molecular and cellular functions. There were a total of 212 significantly dysregulated genes, several of which are involved in the regulation of proteasomal function and NF-κB signaling cascade. Findings of the gene expression study were validated by using quantitative reverse transcriptase polymerase chain reaction analyses to test genes involved in various signaling cascades. This investigation reveals the importance of the VCPR155H/+ mouse model in the understanding of cellular and molecular mechanisms causing VCP-associated neurodegenerative diseases and in the discovery of novel therapeutic advancements and strategies for patients suffering with these debilitating disorders.
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DOI：
10.1111/j.1752-8062.2012.00407.x
发表时间：
2012-06
期刊：
Clinical and translational science
影响因子：
--
作者：
Nalbandian A;Ghimbovschi S;Radom-Aizik S;Dec E;Vesa J;Martin B;Knoblach S;Smith C;Hoffman E;Kimonis VE
通讯作者：
Kimonis VE
影响因子：
7.8
作者：
Fu, Xinrong;Ng, Christine;Feng, Daorong;Liang, Chun
通讯作者：
Liang, Chun
影响因子：
4.8
作者：
Müller, JMM;Meyer, HH;Shima, DT
通讯作者：
Shima, DT
DOI：
10.1196/annals.1396.020
发表时间：
2007-01-01
期刊：
HEALTHY AGING AND LONGEVITY
影响因子：
--
作者：
Bergamini, Ettore;Cavallini, Gabriella;Gori, Zina
通讯作者：
Gori, Zina
DOI：
10.1083/jcb.114.3.443
发表时间：
1991-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fröhlich KU;Fries HW;Rüdiger M;Erdmann R;Botstein D;Mecke D
通讯作者：
Mecke D