"遗传性端粒综合症"Coats Plus症是一种严重的罕见遗传性早衰疾病，常见症状为视网膜脱落、颅内钙化、骨质缺乏及消化道出血。Coats Plus患者通常携带有CST蛋白复合体组分基因突变，而突变造成的CST复合体功能缺失很可能是Coats Plus症的致病原因。CST蛋白复合体在端粒维持和基因组复制中多个步骤都发挥功能，但是功能机制尤其是其在基因组复制中的功能尚不清楚，因此其不同功能缺失是如何引发Coats Plus症的致病机理还需深入研究。另一方面，Coats Plus症作为典型的多器官早衰疾病，也是研究人类衰老机制的天然模型。本项目将从CST蛋白复合体的功能出发，在端粒维持功能机制研究基础上，着重解析其在基因组复制中的功能，并通过建立疾病突变体和人类胚胎干细胞疾病模型，详细探究CST复合体组分的不同基因突变对干细胞多能性和分化的影响，从而揭示Coats Plus症的致病机理。

The "Inherited telomere syndrome" Coats Plus is a rare genetic disorder where patients present with retinal telangiectasia, intracranial calcifications, osteopenia, and gastrointestinal bleeding. Patients with Coats Plus syndrome usually have mutations in genes encoding subunits of the CST complex and CST dysfunction appears to be the cause of their disease. CST functions in multiple aspects of telomere maintenance and genome-wide resolution of replication stress. However, the mechanisms of CST action, especially its genome-wide roles, remain unclear. To understand the pathogenesis of Coats Plus syndrome, functional studies of CST's various roles are essential. Furthermore, Coats plus syndrome provides a natural model to study human aging because patients show premature disease in multiple organs. We have previously analyzed the telomeric roles of the CST complex. In this study, we will focus on its genome-wide roles in replication. Using patient mutations and human embryonic stem cell models, we will also study the effect of mutations on stem cell pluripotency and differentiation, in order to reveal the pathogenesis of Coats Plus syndrome.