iPSC modelling and multi-omics analysis to understand age-related macular degeneration

iPSC 建模和多组学分析以了解年龄相关性黄斑变性

• 批准号: MR/R024952/1
• 负责人: Rachel Louise Taylor
• 金额: $ 36.82万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR024952%2F1
• 关键词: iPSC; modelling; multi; omics; analysis

Age-related macular degeneration (AMD) is a leading global cause of blindness that affects 8-12% of people over the age of 60 years. It is estimated that by the year 2040, 288 million people will be affected by AMD. As such, it represents one of the biggest economic burdens faced by healthcare services around the world. AMD is a complex condition, caused by a combination of non-modifiable (e.g. increasing age, ethnicity) and modifiable (e.g. obesity, smoking, dietary antioxidant intake) risk factors. Genetic variants also play a significant role in AMD risk, with rare and common polymorphisms in the Complement factor H (CFH) gene accountable for up to 50% increased risk of disease development. Animal and cellular models of AMD are not able to accurately replicate the biological complexities of the condition, thus precluding understanding of the contribution of genetic variants to disease pathogenesis. Consequently, there are very few treatment options available. Early-onset macular degeneration (EOMD) is an important cause of severe and progressive visual loss in young adults that shows very similar disease pathology to AMD. Unlike AMD, EOMD has a much weaker association with life-style related risk factors and is often present in more than one generation of a family suggesting a strong genetic component. Research has shown that rare, deleterious and common AMD-associated DNA changes in the CFH gene underlie EOMD in a proportion of cases. The aim of this project is to study the role of CFH impacting variants disease pathogenesis using induced pluripotent stem cells (iPSC) differentiated in to retinal pigment epithelium (RPE) from EOMD patients. This study will investigate the direct impact of genetic variation on protein function, before employing cutting-edge 'omics methodologies to measure the genome-wide effect of impaired protein function at multiple biological levels. Increased understanding of EOMD biology will shed light on the mechanisms driving AMD onset and progression, and will facilitate the development of treatment strategies. In addition, further insight into the the contribution of genetic variants to disease development will provide more patients and their families with specialised care, precise diagnosis, prognostic information and genetic counselling- crucial in the era of personalised genomic medicine.

年龄相关性黄斑变性（AMD）是全球失明的主要原因，影响到8-12%的60岁以上人群。据估计，到2040年将有2.88亿人受到AMD的影响。因此，它代表了世界各地医疗保健服务面临的最大经济负担之一。AMD是一种复杂的疾病，由不可改变的（如年龄、种族增加）和可改变的（如肥胖、吸烟、饮食抗氧化剂摄入）危险因素共同引起。遗传变异在AMD风险中也起着重要作用，补体因子H （CFH）基因中罕见和常见的多态性可导致疾病发展风险增加50%。AMD的动物和细胞模型不能准确地复制该疾病的生物学复杂性，从而阻碍了对遗传变异对疾病发病机制的贡献的理解。因此，可供选择的治疗方法非常少。早发性黄斑变性（EOMD）是青壮年严重进行性视力丧失的重要原因，其病理与AMD非常相似。与AMD不同的是，EOMD与生活方式相关的风险因素的关联要弱得多，而且通常在一个家庭中不止一代都存在，这表明它有很强的遗传成分。研究表明，在一定比例的病例中，CFH基因中与amd相关的罕见、有害和常见的DNA变化是EOMD的基础。本项目旨在利用EOMD患者视网膜色素上皮（RPE）分化的诱导多能干细胞（iPSC）研究CFH对变异疾病发病机制的影响。本研究将研究遗传变异对蛋白质功能的直接影响，然后采用尖端的组学方法在多个生物学水平上测量蛋白质功能受损的全基因组效应。增加对EOMD生物学的了解将有助于阐明AMD发病和发展的机制，并将促进治疗策略的发展。此外，进一步了解遗传变异对疾病发展的贡献将为更多患者及其家属提供专门护理、精确诊断、预后信息和遗传咨询——这在个性化基因组医学时代至关重要。

项目成果

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

• DOI: 10.1016/j.ajhg.2018.04.014
• 发表时间: 2018-06-07
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Reijnders MRF;Miller KA;Alvi M;Goos JAC;Lees MM;de Burca A;Henderson A;Kraus A;Mikat B;de Vries BBA;Isidor B;Kerr B;Marcelis C;Schluth-Bolard C;Deshpande C;Ruivenkamp CAL;Wieczorek D;Deciphering Developmental Disorders Study;Baralle D;Blair EM;Engels H;Lüdecke HJ;Eason J;Santen GWE;Clayton-Smith J;Chandler K;Tatton-Brown K;Payne K;Helbig K;Radtke K;Nugent KM;Cremer K;Strom TM;Bird LM;Sinnema M;Bitner-Glindzicz M;van Dooren MF;Alders M;Koopmans M;Brick L;Kozenko M;Harline ML;Klaassens M;Steinraths M;Cooper NS;Edery P;Yap P;Terhal PA;van der Spek PJ;Lakeman P;Taylor RL;Littlejohn RO;Pfundt R;Mercimek-Andrews S;Stegmann APA;Kant SG;McLean S;Joss S;Swagemakers SMA;Douzgou S;Wall SA;Küry S;Calpena E;Koelling N;McGowan SJ;Twigg SRF;Mathijssen IMJ;Nellaker C;Brunner HG;Wilkie AOM
• 通讯作者: Wilkie AOM

Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases.

• DOI: 10.1136/jmedgenet-2017-104791
• 发表时间: 2018-03
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Ellingford JM;Horn B;Campbell C;Arno G;Barton S;Tate C;Bhaskar S;Sergouniotis PI;Taylor RL;Carss KJ;Raymond LFL;Michaelides M;Ramsden SC;Webster AR;Black GCM
• 通讯作者: Black GCM

New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease

GRK1相关大口病的新致病变异和致病机制的见解

• DOI: 10.1101/2020.02.20.936880
• 发表时间: 2020
• 作者: Poulter J

An Unusual Retinal Phenotype Associated With a Mutation in Sterol Carrier Protein SCP2.

与甾醇载体蛋白 SCP2 突变相关的异常视网膜表型。

• DOI: 10.1001/jamaophthalmol.2016.4985
• 发表时间: 2017
• 期刊: JAMA ophthalmology
• 影响因子: 8.1
• 作者: Morarji J

Craniosynostosis-microphthalmia syndrome belongs to the spectrum of BCOR-related disorders.

颅缝早闭-小眼症综合征属于 BCOR 相关疾病的范畴。

• DOI: 10.1111/cge.13808
• 发表时间: 2020
• 期刊: Clinical genetics
• 影响因子: 3.5
• 作者: Cinnirella G