Gene regulation, genetic mechanisms and development of potential therapies for corneal endothelial dystrophies

角膜内皮营养不良的基因调控、遗传机制和潜在疗法的开发

• 批准号: MR/S031820/1
• 负责人: Alice Davidson
• 金额: $ 122.12万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS031820%2F1
• 关键词: Gene; regulation; genetic; mechanisms; development

Background and need for the research: The cornea is the transparent window situated at the front of the eye. It protects the eye from the external environment and focuses light onto the retina. The inner most part of this tissue is comprised of a specialised layer of corneal endothelial cells. These cells perform a pump-like mechanism removing water from the outer layers of the cornea, to ensure that the tissue is optimally hydrated, and regulate the movement of crucial nutrients into the rest of the cornea. The term 'corneal endothelial dystrophies (CEDs)' describes a group of diseases that lead to dysfunction of this specialised cellular layer. Patients with CEDs experience corneal swelling and clouding, due to endothelial cell dysfunction, leading to impaired vision. In some patients, glaucoma develops, that further increases the likelihood of visual impairment and/or blindness. Fuchs endothelial corneal dystrophy (FECD) is an age-related disease and by far the most common CED, affecting 4.5% of people >50 years of age. Other much rarer types of CEDs include a disorder called posterior polymorphous corneal dystrophy (PPCD). In recent years, there has been much progress in understanding the genetic causes of CEDs and we now know certain genetic faults, known as mutations, in several different genes are responsible for disease. However, we still do not fully understand the underlying biological basis of these diseases, and >20% of cases still remain genetically unexplained. Corneal transplantation is currently the only treatment option available for CED patients experiencing visual loss, but the long-term survival of grafts is poor. Surgery also relies upon specialist facilities and healthy donor corneas, of which there is a currently a global shortage. Only by understanding how the mutations alter the normal functioning of the corneal endothelium, can appropriate new therapeutic strategies be developed to address the urgent clinical need for alternative treatment options. Aim: This research program aims to 1) identify the genetic cause of disease in unsolved CED cases and 2) investigate how and why different CED-associated mutations cause endothelial cell dysfunction and 3) use this knowledge to develop new therapies. Methods: DNA samples from CED patients will be analysed using a range of genetic sequencing methods to identify genetic origins of disease. In parallel, using donated tissue removed during planned corneal transplant surgery, I will use techniques that I have established in the laboratory to grow and maintain the corneal endothelial cells, to enable investigation of how and why particular mutations cause cellular dysfunction and disease. This knowledge will be harnessed to design gene-directed treatment strategies. Endothelial cell cultures established from diseased patients tissue will act as the ideal model system to test the efficacy of different treatment strategies in a safe and disease relevant context. Expected outcomes of the study: This study will identify genetic causes of CEDs that will in the short term facilitate earlier pre-symptomatic detection of disease in affected families, inform genetic counselling and may alter the clinical management of disease. In parallel, cellular mechanisms of corneal disease will be investigated to enhance understanding of the biological reasons for disease to enable effective non-surgical treatments to be developed for these sight threatening conditions. Knowledge gained will also impact upon the areas of personalised medicine, age-related disease, and human genetics.

研究背景和需要：角膜是位于眼睛前部的透明窗口。它保护眼睛免受外部环境的影响，并将光线聚焦到视网膜上。该组织的最内部部分由角膜内皮细胞的特化层组成。这些细胞执行类似泵的机制，从角膜外层去除水分，以确保组织得到最佳水合，并调节关键营养物质进入角膜其余部分的运动。术语"角膜内皮营养不良（CED）"描述了一组导致该专门细胞层功能障碍的疾病。患有CED的患者由于内皮细胞功能障碍而经历角膜肿胀和混浊，导致视力受损。在一些患者中，青光眼发展，这进一步增加了视力损害和/或失明的可能性。Fuchs角膜内皮营养不良（FECD）是一种年龄相关性疾病，是迄今为止最常见的CED，影响4.5%的> 50岁的人群。其他更罕见的CED类型包括一种称为后多形角膜营养不良（PPCD）的疾病。近年来，在了解CED的遗传原因方面取得了很大进展，我们现在知道几个不同基因中的某些遗传缺陷（称为突变）是导致疾病的原因。然而，我们仍然没有完全了解这些疾病的潜在生物学基础，超过20%的病例仍然无法解释遗传学原因。角膜移植是目前CED患者视力丧失的唯一治疗选择，但移植物的长期存活率很差。手术还依赖于专业设施和健康的供体角膜，目前全球都存在短缺。只有了解这些突变如何改变角膜内皮的正常功能，才能开发出适当的新治疗策略，以满足临床对替代治疗方案的迫切需求。目的：该研究项目旨在1）确定未解决的CED病例中疾病的遗传原因，2）研究不同的CED相关突变如何以及为什么会导致内皮细胞功能障碍，3）利用这些知识开发新的疗法。方法：将使用一系列基因测序方法分析CED患者的DNA样本，以确定疾病的遗传起源。同时，使用在计划的角膜移植手术中取出的捐赠组织，我将使用我在实验室建立的技术来生长和维持角膜内皮细胞，以研究特定突变如何以及为什么会导致细胞功能障碍和疾病。这些知识将被用来设计基因导向的治疗策略。从患病患者组织建立的内皮细胞培养物将作为理想的模型系统，以在安全和疾病相关的背景下测试不同治疗策略的功效。这项研究的预期成果：这项研究将确定CED的遗传原因，这将在短期内促进受影响家庭中疾病的早期症状前检测，为遗传咨询提供信息，并可能改变疾病的临床管理。同时，将研究角膜疾病的细胞机制，以加强对疾病生物学原因的理解，从而为这些威胁视力的疾病开发有效的非手术治疗方法。获得的知识也将影响个性化医疗，年龄相关疾病和人类遗传学领域。

项目成果

Should Patients with Kearns-Sayre Syndrome and Corneal Endothelial Failure Be Genotyped for a TCF4 Trinucleotide Repeat, Commonly Associated with Fuchs Endothelial Corneal Dystrophy?

• DOI: 10.3390/genes12121918
• 发表时间: 2021-11-29
• 期刊: Genes
• 影响因子: 3.5
• 作者: Dudakova L;Skalicka P;Davidson AE;Sadan AN;Chylova M;Jahnova H;Anteneova N;Tesarova M;Honzik T;Liskova P
• 通讯作者: Liskova P

Disruption of OVOL2 Distal Regulatory Elements as a Possible Mechanism Implicated in Corneal Endothelial Dystrophy

OVOL2 远端调节元件的破坏是角膜内皮营养不良的可能机制

• DOI: 10.1155/2024/4450082
• 发表时间: 2024
• 期刊: Human Mutation
• 影响因子: 3.9
• 作者: Dudakova L

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

• DOI: 10.1038/s42003-021-01784-0
• 发表时间: 2021-03-01
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Hardcastle AJ;Liskova P;Bykhovskaya Y;McComish BJ;Davidson AE;Inglehearn CF;Li X;Choquet H;Habeeb M;Lucas SEM;Sahebjada S;Pontikos N;Lopez KER;Khawaja AP;Ali M;Dudakova L;Skalicka P;Van Dooren BTH;Geerards AJM;Haudum CW;Faro VL;Tenen A;Simcoe MJ;Patasova K;Yarrand D;Yin J;Siddiqui S;Rice A;Farraj LA;Chen YI;Rahi JS;Krauss RM;Theusch E;Charlesworth JC;Szczotka-Flynn L;Toomes C;Meester-Smoor MA;Richardson AJ;Mitchell PA;Taylor KD;Melles RB;Aldave AJ;Mills RA;Cao K;Chan E;Daniell MD;Wang JJ;Rotter JI;Hewitt AW;MacGregor S;Klaver CCW;Ramdas WD;Craig JE;Iyengar SK;O'Brart D;Jorgenson E;Baird PN;Rabinowitz YS;Burdon KP;Hammond CJ;Tuft SJ;Hysi PG
• 通讯作者: Hysi PG

TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease.

• DOI: 10.1016/j.preteyeres.2020.100883
• 发表时间: 2021-03
• 期刊: Progress in retinal and eye research
• 影响因子: 17.8
• 作者: Fautsch MP;Wieben ED;Baratz KH;Bhattacharyya N;Sadan AN;Hafford-Tear NJ;Tuft SJ;Davidson AE
• 通讯作者: Davidson AE

Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles.

• DOI: 10.3390/genes12050677
• 发表时间: 2021-04-30
• 期刊: Genes
• 影响因子: 3.5
• 作者: Dudakova L;Stranecky V;Piherova L;Palecek T;Pontikos N;Kmoch S;Skalicka P;Vaneckova M;Davidson AE;Liskova P
• 通讯作者: Liskova P