The ultrastructural basis of corneal dysfunction and the development and optimization of novel therapeutic strategies

角膜是眼睛前部的透明窗口，是眼睛的主要聚焦元件。为了发挥其作用，它必须非常透明，非常坚固和精确成形。角膜的透明度、强度和形状都是由组成角膜的胶原纤维和它们之间的小分子控制的。这发生在从分子水平向上的不同结构水平上：胶原蛋白分子形成原纤维，原纤维又形成更大的结构，称为层片，然后堆叠起来形成组织本身。从我们以前的工作和其他人所做的工作中，我们知道了很多关于为什么角膜是透明的，并开始了解胶原蛋白层的排列，从而产生角膜的形状和聚焦能力。然而，确切的细节仍然未知，并且直到它们被知道，才可能理解为什么在角膜的许多疾病中，或在角膜上的不同类型的手术（包括激光手术）之后，透明度、强度和/或形状是异常的，并且视力丧失或非常模糊。我们将使用一些新的和令人兴奋的三维生物成像和强大的X射线测量技术，解释胶原纤维和细胞如何在角膜中排列，使其透明，以及其他蛋白质如何控制这种排列。我们还将在更高的结构层次上解释薄板是如何排列以提供形式和强度的。这将使我们能够构建计算机模型，从中预测给定手术切口或其他治疗后角膜形状的变化，以帮助外科医生。然后，我们将解释在几种重要的角膜疾病中出现的问题，并研究预防或纠正这些变化的方法，例如通过使用干细胞治疗或蛋白质交联。这些方法还将使我们能够解释为什么当角膜受伤时，组织强度和透明度会受到损害。同样，将研究改善这种伤口愈合的方法，例如上文提到的那些方法，目的是在保持透明度的同时增强角膜。最后，不同国家的几个研究小组正试图开发生物人工角膜，因为世界范围内用于移植手术的供体角膜组织短缺，而且很可能继续短缺。合成生物学依赖于理解自然界如何利用组织的成分来实现其重要特性。在角膜的情况下，我们将通过阐明结构和功能之间的确切关系获得的知识将是无价的，并将使我们能够与这些小组合作，更快地将他们的结构推向功能齐全的人工角膜。

The cornea is the transparent window at the front of the eye and is its main focussing element. To fulfil its role it has to be very transparent, very strong and precisely shaped. Transparency, strength and shape are all controlled by the collagen fibrils that make up the cornea, and by the small molecules between them. This happens at different structural levels from the molecular level upwards: collagen molecules form fibrils, which in turn form larger structures called lamellae, which are then stacked up to form the tissue itself. From our previous work and work done by others, we know a lot about why the cornea is transparent and are beginning to understand the arrangement of collagen lamellae that gives rise to the cornea's shape and thus its focusing abilities. However, the precise details are still not known and, until they are, it will not be possible to understand why, in numerous diseases of the cornea, or after different types of surgery on the cornea - including laser surgery - transparency, strength and/or shape are abnormal and vision is lost or very blurred. We will use several new and exciting 3-D biological imaging and powerful X-ray measuring techniques, to explain how collagen fibrils and cells are arranged in the cornea to make it transparent, and how other proteins control this arrangement. We will also explain at a higher structural level how lamellae are arranged to provide form and strength. This will allow us to construct computer models from which to predict changes in corneal shape following given surgical incisions or other treatments to help inform surgeons. We will then explain what goes wrong in several important corneal diseases and investigate methods of preventing or correcting these changes, for example by using stem cell therapy or protein crosslinking. The methods will also allow us to explain why, when the cornea is wounded, tissue strength and transparency are compromised. Again, methods to improve this wound healing such as those mentioned above will be investigated, with the aim of strengthening the cornea whilst preserving transparency. Finally, several research groups in different countries are trying to develop a biological artificial cornea as there is, and is likely to continue to be, a worldwide shortage of donor corneal tissue for graft surgery. Synthetic biology depends on understanding how nature utilises the constituents of a tissue to achieve its vital properties. In the case of the cornea, the knowledge that we will obtain by elucidating the exact relationship between structure and function will be invaluable, and will allow us to collaborate with these groups to drive their constructs more quickly towards a fully functioning artificial cornea.