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首页> 美国卫生研究院文献>other >Proteomic profiling of TGFBI-null mouse corneas reveals only minor changes in matrix composition supportive of TGFBI knockdown as therapy against TGFBI-linked corneal dystrophies
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Proteomic profiling of TGFBI-null mouse corneas reveals only minor changes in matrix composition supportive of TGFBI knockdown as therapy against TGFBI-linked corneal dystrophies

机译：TGFBI无效的小鼠角膜的蛋白质组学分析显示支持TGFBI敲除的基质成分仅有微小变化可用于治疗TGFBI相关的角膜营养不良

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TGFBIp is a constituent of the extracellular matrix in many human tissues including the cornea, where it is one of the most abundant proteins expressed. TGFBIp interacts with Type I, II, IV, VI and XII collagens as well as several members of the integrin family, suggesting it plays an important role in maintaining structural integrity and possibly corneal transparency as well. Significantly, more than 60 point mutations within the TGFBI gene have been reported to result in aberrant TGFBIp folding and aggregation in the cornea, resulting in severe visual impairment and blindness. Several studies have focused on targeting TGFBIp in the cornea as a therapeutic approach to treat TGFBI-linked corneal dystrophies, but the effect of this approach on corneal homeostasis and matrix integrity remained unknown. In the current study, we evaluated the histological and proteomic profiles of corneas from TGFBI-deficient mice as well as potential redundant functions of the paralogous protein POSTN. The absence of TGFBIp in mouse corneas did not grossly affect the collagen scaffold, and POSTN is unable to compensate for loss of TGFBIp. Proteomic comparison of wildtype and TGFBI−/− mice revealed 11 proteins were differentially regulated, including Type VI and XII collagens. However, as these alterations did not manifest at the macroscopic and behavioral levels, these data support partial or complete TGFBI knockdown as a potential therapy against TGFBI-linked corneal dystrophies. Lastly, in situ hybridization verified TGFBI mRNA in the epithelial cells but not in other cell types, supportive of a therapy directed specifically at this lineage.
机译：TGFBIp是许多人类组织（包括角膜）中细胞外基质的组成部分，在角膜中，它是表达最丰富的蛋白质之一。 TGFBIp与I，II，IV，VI和XII型胶原蛋白以及整联蛋白家族的几个成员相互作用，这表明它在维持结构完整性和可能的​​角膜透明性方面也起着重要作用。值得注意的是，据报道，TGFBI基因内超过60个点突变导致TGFBIp在角膜中异常折叠和聚集，从而导致严重的视力障碍和失明。几项研究集中于针对角膜中的TGFBIp作为治疗与TGFBI相关的角膜营养不良的治疗方法，但是这种方法对角膜稳态和基质完整性的影响仍然未知。在当前的研究中，我们评估了来自TGFBI缺陷小鼠的角膜的组织学和蛋白质组学特征以及旁源蛋白POSTN的潜在冗余功能。小鼠角膜中缺乏TGFBIp不会严重影响胶原蛋白支架，POSTN无法弥补TGFBIp的损失。对野生型和TGFBI -/-小鼠进行蛋白质组学比较，发现11种蛋白质被差异调节，包括VI型和XII型胶原。但是，由于这些改变在宏观和行为水平上均未显现，因此这些数据支持将TGFBI敲除部分或全部，作为针对TGFBI相关的角膜营养不良的潜在疗法。最后，原位杂交在上皮细胞中证实了TGFBI mRNA，但在其他细胞类型中未证实，这支持了针对该谱系的疗法。

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