TIPARP-AS1对小梁网和Schlemm管的作用及其机制的研究

Glaucoma is the top reason for blindness all over the world. Primary open angle glaucoma (POAG) is the most common type of glaucoma, which is a complex disease with genetic heterogeneity. Most POAG cases are sporadic, some may also present as a median trait in pedigrees. Up to now, the contribution of reported genes to POAG is still limited and most POAG cases can not be explained yet. We discovered a mutation of c.T719A on TIPARP-AS1 gene segregated with the phenotype of a large POAG pedigree, which suggested TIPARP-AS1 might be a disease causing gene of POAG. TIPARP-AS1 locates at the antisense strand at the beginning of TIPARP gene. TIPARP-AS1 plays a role of regulation on TIPARP. TIPARP is a member of PARP family. The ADP-ribosylation catalyzed by TIPARP is an important protein modification mechanism after translation, which plays a significant role in many pathological process. However, the role of TIPARP-AS1 and TIPARP in intraocular pressure regulation and POAG development is unclear. In this project, we aim to investigate how TIPARP-AS1 regulates its target gene TIPARP and its downstream molecules and how it affects the function of trabecular meshwork (TM) and Schlemm canal (SC) and the possible underlying molecular mechanism. We propose to prove the contribution of TIPARP-AS1 to the development of POAG by clarify the function of TIPARP-AS1, in order to understand the mechanism of glaucoma in further and provide theory evidence for novel method of diagnosis and treatment.

青光眼是全球第一大不可逆致盲眼病，原发性开角型青光眼（POAG）是青光眼中最主要的一种类型，是具有遗传异质性的复杂疾病。迄今为止，青光眼的已知基因仍不能解释大多数POAG患者的发病。申请人前期通过一个青光眼大家系发现TIPARP-AS1基因可能是POAG的致病基因。TIPARP-AS1是位于TIPARP起始端反义链的长链非编码RNA（LncRNA），对靶基因TIPARP起着调控作用。TIPARP催化的ADP-核糖基化是重要的蛋白质翻译后修饰机制，在多种病理过程中发挥重要作用，然而在眼压调控及青光眼的发病机制中所起的作用尚不清楚。本项目旨在通过研究TIPARP-AS1基因是如何通过调控其靶基因TIPARP及下游分子，进而对小梁网和Schlemm管的功能产生影响，来揭示TIPARP-AS1在POAG发生过程中所起的作用，为进一步深入理解青光眼的发病机制，研究新的诊疗方法提供理论依据。