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人斜视眼外肌肌肉和肌腱中的蛋白质组成和基因表达

Agarwal AB, Feng CY, Altick AL, et al.

期刊名称:Investigative ophthalmology & visual science

卷期:2016年第57卷第13期

摘要

目的:旨在确定人斜视眼外肌中结构性蛋白质组成和关键调控基因的表达是否发生改变。方法:在收集斜视手术中斜视水平眼外肌样本,并与器官捐献者的正常肌肉进行比较。我们使用蛋白质组学,标准和定制PCR阵列和微阵列来确定主要结构蛋白的变化和基因表达的变化。我们重点研究了肌肉和结缔组织及其通过酶,生长因子和细胞因子的控制。结果:研究显示,斜视肌的肌球蛋白,原肌球蛋白,肌钙蛋白和滴度下调。胶原蛋白的表达与胶原蛋白合成和降解调节剂----胶原酶基质金属蛋白酶(MMP2及其抑制剂,金属蛋白酶组织抑制剂(TIMP1TIMP2与肿瘤坏死因子(TNF),TNF受体和结缔组织生长因子(CTGF)以及蛋白聚糖出现上调。控制细胞外基质(ECM)的生长因子也出现上调。PCR阵列检测的410个信号基因中,在斜视表型中具有下调作用的分子包括GDNFNRG1PAX7; CTGFCXCR4NPY1RTNFNTRK1NTRK2均出现上调。已知可控制眼外肌可塑性的信号分子主要在肌腱而不是肌肉中表达。两个水平的肌肉,内侧和外侧直肌的蛋白质和基因表达变化相似,并且没有明显的年龄影响。结论:蛋白质定量和基因表达显示斜视患者眼外肌组成存在显著差异,如重要的运动蛋白,ECM组成和结缔组织。因此,我们的研究支持斜视肌分子组成发生显着改变的新观点。

Purpose:To determine whether structural protein composition and expression of key regulatory genes are altered in strabismic human extraocular muscles.Methods:Samples from strabismic horizontal extraocular muscles were obtained during strabismus surgery and compared with normal muscles from organ donors. We used proteomics, standard and customized PCR arrays, and microarrays to identify changes in major structural proteins and changes in gene expression. We focused on muscle and connective tissue and its control by enzymes, growth factors, and cytokines.Results:Strabismic muscles showed downregulation of myosins, tropomyosins, troponins, and titin. Expression of collagens and regulators of collagen synthesis and degradation, the collagenase matrix metalloproteinase (MMP)2 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2, was upregulated, along with tumor necrosis factor (TNF), TNF receptors, and connective tissue growth factor (CTGF), as well as proteoglycans. Growth factors controlling extracellular matrix (ECM) were also upregulated. Among 410 signaling genes examined by PCR arrays, molecules with downregulation in the strabismic phenotype included GDNF, NRG1, and PAX7; CTGF, CXCR4, NPY1R, TNF, NTRK1, and NTRK2 were upregulated. Signaling molecules known to control extraocular muscle plasticity were predominantly expressed in the tendon rather than the muscle component. The two horizontal muscles, medial and lateral rectus, displayed similar changes in protein and gene expression, and no obvious effect of age.Conclusions:Quantification of proteins and gene expression showed significant differences in the composition of extraocular muscles of strabismic patients with respect to important motor proteins, elements of the ECM, and connective tissue. Therefore, our study supports the emerging view that the molecular composition of strabismic muscles is substantially altered.


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