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

年龄相关性黄斑变性(AMD)是全球主要的致盲原因，60岁以上的人中有8%-12%受到影响。据估计，到2040年，2.88亿人将受到AMD的影响。因此，它代表着世界各地医疗服务面临的最大经济负担之一。AMD是一种复杂的疾病，由不可改变的危险因素(如年龄、种族增加)和可改变的危险因素(如肥胖、吸烟、饮食抗氧化剂摄入量)共同引起。遗传变异也在AMD风险中发挥重要作用，补体因子H(CFH)基因罕见和常见的多态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复制这种疾病的生物学复杂性，从而排除了对遗传变异在疾病发病机制中的作用的理解。因此，可供选择的治疗方法很少。早发性黄斑变性(EOMD)是导致青壮年严重进行性视力丧失的重要原因，其发病机制与AMD非常相似。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，而且通常存在于一个家庭的不止一代人中，这表明有很强的遗传成分。研究表明，在部分病例中，CFH基因罕见的、有害的和常见的AMD相关DNA变化是EOMD的基础。本项目的目的是利用EOMD患者的诱导多能干细胞(IPSC)分化为视网膜色素上皮(RPE)，研究CFH在各种疾病发病机制中的作用。这项研究将调查遗传变异对蛋白质功能的直接影响，然后使用尖端的组学方法在多个生物水平上测量蛋白质功能受损的全基因组影响。对EOMD生物学的更多了解将有助于揭示AMD发病和进展的机制，并将促进治疗策略的开发。此外，进一步了解基因变异对疾病发展的贡献将为更多的患者及其家人提供专门的护理、准确的诊断、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.