Towards a functional understanding of proteoglycan-collagen associations in the cornea by 3-dimensional electron microscopy of gene-targeted mutants

通过基因靶向突变体的 3 维电子显微镜对角膜中蛋白多糖-胶原蛋白关联的功能性理解

• 批准号: BB/F022077/1
• 负责人: Carlo Knupp
• 金额: $ 39.5万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF022077%2F1
• 关键词: Towards; functional; understanding; proteoglycan; collagen

The cornea is the front clear part of the eye. It is essential for proper vision because it lets in light and focuses it on the retina at the back of the eye. Thus, a sharp image is formed and we can see properly. The cornea is a special tissue because it is transparent, and in this respect it is unlike other related tissues in the body -- the tendons that link our bones and muscles or the sclera (the white of the eye), for example -- which are made of similar components. Scientists believe that the cornea is transparent because the protein called collagen that forms much of the cornea is mostly in the form of long, thin rope-like structures called fibrils. Moreover, these collagen fibrils are formed into a very well defined arrangement that lets light through. If this arrangement breaks down the cornea looses its transparency and becomes cloudy. As a result, vision is severely compromised. Interestingly, scientists suspect that molecules called proteoglycans in the cornea influence the collagen fibrils and force them to take up the special arrangement that allows corneal transparency. Previous investigations have studied the structural relationship between collagen and proteoglycans using the corneas of mice that have been genetically modified so that they don't possess certain types of proteoglycan. This allows the structure of different proteoglycan sub-types to be understood. But, up to now it has only been possible to study the collagen and proteoglycan structures in 2 dimensions by examining very thin sections of cornea on an electron microscope, so the understanding that we can get is limited. Now, however, we are able to use a new modification of electron microscopy to produce images of the collagen and proteoglycans that allows us to see their structures in 3 dimensions. This project will thus discover the links between collagen and proteoglycans in the cornea in a detail not seen previously, and will help us to understand how the structure and transparency of the cornea is maintained.

角膜是眼睛前部透明的部分。它对正常视力至关重要，因为它让光线进入并聚焦在眼睛后部的视网膜上。这样，就形成了一个清晰的图像，我们可以正确地看到。角膜是一种特殊的组织，因为它是透明的，在这方面，它不同于身体中的其他相关组织，例如连接骨骼和肌肉的肌腱或巩膜（眼睛的白色部分），它们由类似的成分组成。科学家们认为角膜是透明的，因为构成角膜大部分的胶原蛋白主要是长而细的绳状结构，称为原纤维。此外，这些胶原原纤维形成了一个非常明确的排列，让光线通过。如果这种排列被破坏，角膜就会失去透明度，变得浑浊。因此，视力严重受损。有趣的是，科学家们怀疑角膜中一种叫做蛋白聚糖的分子会影响胶原原纤维，迫使它们采取特殊的排列方式，从而使角膜透明。先前的研究已经研究了胶原蛋白和蛋白多糖之间的结构关系，使用的是经过基因改造的老鼠的角膜，这样它们就不含有某些类型的蛋白多糖。这使得不同蛋白聚糖亚型的结构得以理解。但是，到目前为止，只能通过在电子显微镜下观察非常薄的角膜切片来研究胶原蛋白和蛋白多糖的二维结构，所以我们能得到的理解是有限的。然而，现在，我们能够使用一种新的电子显微镜来产生胶原蛋白和蛋白聚糖的图像，使我们能够看到它们的三维结构。因此，该项目将以前所未有的细节发现角膜中胶原蛋白和蛋白多糖之间的联系，并将帮助我们了解角膜的结构和透明度是如何维持的。

项目成果

Large proteoglycan complexes and disturbed collagen architecture in the corneal extracellular matrix of mucopolysaccharidosis type VII (Sly syndrome).

• DOI: 10.1167/iovs.11-7377
• 发表时间: 2011-08
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: R. Young;P. Lišková;C. Pinali;B. Palka;M. Palos;K. Jirsova;E. Hrdličková;M. Tesařová;M. Elleder;J. Zeman;K. Meek;C. Knupp;A. Quantock

Electron tomography reveals multiple self-association of chondroitin sulphate/dermatan sulphate proteoglycans in Chst5-null mouse corneas.

电子断层扫描显示 Chst5 缺失小鼠角膜中硫酸软骨素/硫酸皮肤素蛋白聚糖的多重自关联。

• DOI: 10.1016/j.jsb.2011.03.015
• 发表时间: 2011
• 期刊: Journal of structural biology
• 影响因子: 3
• 作者: Parfitt GJ

A comparison of glycosaminoglycan distributions, keratan sulphate sulphation patterns and collagen fibril architecture from central to peripheral regions of the bovine cornea.

• DOI: 10.1016/j.matbio.2014.06.004
• 发表时间: 2014-09
• 期刊: MATRIX BIOLOGY
• 影响因子: 6.9
• 作者: Ho, Leona T. Y.;Harris, Anthony M.;Tanioka, Hidetoshi;Yagi, Naoto;Kinoshita, Shigeru;Caterson, Bruce;Quantock, Andrew J.;Young, Robert D.;Meek, Keith M.
• 通讯作者: Meek, Keith M.