A mechanistic understanding of corneal pathobiology and the development of therapeutic strategies for the treatment of connective tissue disorders

对角膜病理学的机制理解和结缔组织疾病治疗策略的开发

• 批准号: MR/S037829/1
• 负责人: Andrew Quantock
• 金额: $ 246.93万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS037829%2F1
• 关键词: mechanistic; understanding; corneal; pathobiology; development

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 transparent, strong and precisely shaped. Transparency and strength are controlled by the collagen fibrils that make up the cornea, and by the small molecules between them. Shape is also controlled by the collagen arrangement, but we have now discovered a complex system of small elastic fibres that we believe helps to restore shape when the cornea is distorted, for example as blood is pumped round the body, during blinking or after eye rubbing. These properties of the cornea are controlled at different structural levels: collagen molecules form fibrils, which in turn form larger structures called lamellae, which are then stacked up to form the tissue itself. Elastic fibres that contain the protein elastin are concentrated around the edge of the cornea in the form of sheets, which we have shown are connected across the human cornea by fine filaments rich in proteins called fibrillins. We want to test our hypothesis that this arrangement allows distortion and recovery mainly at the edge of the cornea, maintaining the shape of the central cornea that controls the focussing of the incoming light. From previous work by us and others, we know a lot about why the cornea is transparent and are beginning to understand the arrangement of collagen lamellae and elastic fibres that gives rise to the cornea's shape and thus its focusing abilities. However, the contribution of different elements of the structure to the overall function is still not known and, until we elucidate this, it will not be possible to understand why, in numerous diseases of the cornea, or after different types of surgery on the cornea, transparency, strength and/or shape are abnormal and vision is lost or very blurred. We have pioneered the use of several sophisticated techniques to study the cornea at every structural level from the molecules upwards: x-ray scattering, serial block face scanning electron microscopy and two photon fluorescence light microscopy. We propose now to build equipment that will allow us to measure which constituents of the structure change when the cornea is distorted by known forces, either during its normal functioning or due to disease and/or surgery. We will also explain how lamellae are arranged to provide form and strength, how the elastic fibres are structured in different parts of the cornea, and what role they play in health and disease. We showed that abnormalities of the elastic fibres occur in corneal diseases such as keratoconus, and we will test our idea that they play a role in other diseases of the eye, such as glaucoma. In addition, we will investigate treatments for corneal disorders, for example by developing new chemical crosslinking methods. To address the world-wide shortage of donor corneas, biological artificial corneas are being developed. However, for corneal replacements to function normally, we must fully understand how nature utilises the constituents of a tissue to achieve its vital properties. This means elucidating the exact relationships between its various components and its function, including how cells communicate with other cells during development, wound healing and tissue regeneration. In the case of the cornea, the knowledge that we will obtain by discovering the exact relationship between its various structural components and its function is crucial for our understanding of corneal transparency and biomechanical stability as related to corneal development, surgical manipulation and implantation, and tissue engineering. Finally, we will demonstrate how cornea is an excellent model system for connective tissues more generally, by collaborating with other groups around the world, using our new techniques to aid our understanding of function/dysfunction in other parts of the body.

角膜是眼睛前部的透明窗口，是它的主要聚焦元素。为了发挥其作用，它必须是透明的、强大的和精确的。角膜的透明度和强度是由构成角膜的胶原原纤维和它们之间的小分子控制的。形状也受胶原蛋白排列的控制，但我们现在发现了一个复杂的小弹性纤维系统，我们相信它有助于在角膜变形时恢复形状，例如当血液被泵到全身时，在眨眼或擦眼后。角膜的这些特性在不同的结构水平上受到控制：胶原分子形成原纤维，原纤维反过来形成更大的结构，称为片层，然后堆叠起来形成组织本身。含有弹性蛋白的弹性纤维以薄片的形式集中在角膜边缘，我们已经展示了这些薄片是通过富含纤维蛋白的细丝在人类角膜上连接起来的。我们想测试我们的假设，这种排列允许主要在角膜边缘的变形和恢复，保持控制入射光聚焦的中央角膜的形状。从我们和其他人之前的工作中，我们知道了很多关于为什么角膜是透明的，并开始理解胶原层和弹性纤维的排列，它们形成了角膜的形状，从而产生了它的聚焦能力。然而，结构的不同元素对整体功能的贡献仍然是未知的，直到我们阐明这一点，才可能理解为什么在许多角膜疾病中，或在不同类型的角膜手术后，透明度，强度和/或形状不正常，视力丧失或非常模糊。我们率先使用了几种复杂的技术来研究角膜从分子向上的每个结构水平：x射线散射，连续块面扫描电子显微镜和双光子荧光显微镜。我们现在建议建造一种设备，使我们能够测量当角膜被已知的力量扭曲时，结构的哪些成分发生了变化，无论是在其正常功能期间还是由于疾病和/或手术。我们还将解释薄层如何排列以提供形状和强度，弹性纤维如何在角膜的不同部位结构，以及它们在健康和疾病中起什么作用。我们发现弹性纤维的异常发生在圆锥角膜等角膜疾病中，我们将验证我们的观点，即它们在青光眼等其他眼部疾病中也起作用。此外，我们将研究角膜疾病的治疗方法，例如开发新的化学交联方法。为了解决世界范围内角膜供体短缺的问题，人们正在开发生物人工角膜。然而，为了使角膜替代物正常发挥作用，我们必须充分了解大自然是如何利用组织的成分来实现其重要特性的。这意味着阐明其各种成分及其功能之间的确切关系，包括细胞在发育、伤口愈合和组织再生过程中如何与其他细胞交流。就角膜而言，我们将通过发现其各种结构成分与其功能之间的确切关系而获得的知识，对于我们理解与角膜发育、手术操作和植入以及组织工程相关的角膜透明度和生物力学稳定性至关重要。最后，我们将通过与世界各地的其他小组合作，使用我们的新技术来帮助我们了解身体其他部位的功能/功能障碍，从而证明角膜是一个更普遍的结缔组织的优秀模型系统。

项目成果

Keratoconus: cross-linking the window of the eye.

• DOI: 10.1177/26330040211003573
• 发表时间: 2021-01
• 期刊: Therapeutic advances in rare disease
• 作者: Hayes, Sally;Morgan, Sian R;Meek, Keith M
• 通讯作者: Meek, Keith M

Microstructural Characterization of Resistance Artery Remodelling in Diabetes Mellitus.

糖尿病阻力动脉重塑的微观结构特征。

• DOI: 10.1159/000517856
• 发表时间: 2022
• 期刊: Journal of vascular research
• 影响因子: 1.7
• 作者: Bell JS

Tropocollagen springs allow collagen fibrils to stretch elastically.

• DOI: 10.1016/j.actbio.2022.01.041
• 发表时间: 2022-04-01
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Bell JS;Hayes S;Whitford C;Sanchez-Weatherby J;Shebanova O;Terrill NJ;Sørensen TLM;Elsheikh A;Meek KM
• 通讯作者: Meek KM

Diffusion Depth and Efficacy of Different Infiltration Times for Rose Bengal/Green Light Corneal Cross-linking in Rabbit Eyes.

兔眼中孟加拉红/绿光角膜交联的扩散深度和不同渗透时间的功效。

• DOI: 10.3928/1081597x-20230726-01
• 发表时间: 2023
• 期刊: 1995)
• 作者: Gao R