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

视网膜相关性黄斑变性（AMD）是全球主要的致盲原因，影响8%-12%的60岁以上的人。据估计，到2040年，将有2.88亿人受到AMD的影响。因此，它是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（例如年龄增加，种族）和可改变的（例如肥胖，吸烟，膳食抗氧化剂摄入）风险因素的组合引起。遗传变异也在AMD风险中发挥重要作用，补体因子H（CFH）基因中的罕见和常见多态性导致疾病发展风险增加高达50%。AMD的动物和细胞模型不能准确地复制该病症的生物学复杂性，因此排除了对遗传变异对疾病发病机制的贡献的理解。因此，可用的治疗选择很少。早发性黄斑变性（EOMD）是年轻成人中严重和进行性视力丧失的重要原因，其显示出与AMD非常相似的疾病病理学。与AMD不同，EOMD与生活方式相关的风险因素的关联性要弱得多，并且通常存在于一个家庭的多代人中，这表明有很强的遗传成分。研究表明，在一定比例的病例中，CFH基因中罕见的、有害的和常见的AMD相关DNA变化是EOMD的基础。该项目的目的是使用来自EOMD患者的诱导多能干细胞（iPSC）分化为视网膜色素上皮（RPE）来研究CFH影响变体疾病发病机制的作用。本研究将调查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水平上测量受损蛋白质功能的全基因组效应。对EOMD生物学的进一步了解将有助于阐明AMD发病和进展的机制，并将促进治疗策略的发展。此外，进一步深入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业护理，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。

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.