原发性卵巢功能不全（POI）是育龄期女性最常见的生殖内分泌疾病之一,遗传因素在发生过程起着主要作用。申请人一直从事POI发病机制的研究工作，在致病基因发现及功能研究方面取得多项进展，发表SCI论文30篇，包括Am J Hum Genet，Hum Mol Genet等杂志。获全国百篇优秀博士学位论文、教育部新世纪优秀人才称号。承担国家自然基金3项。.前期研究发现miR-379-5p、lncRNA1、lncRNA9在POI患者颗粒细胞中表达显著上调，可能共同调控DNA损伤修复基因XRCC6和PARP1。推测在非编码RNA的调控下，XRCC6和PARP1表达异常，DNA损伤修复功能受损，导致卵泡异常闭锁。本项目探讨miR-375-5p、lncRNA1、lncRNA9对XRCC6、PARP1的调控作用及机制，从表观遗传角度阐明DNA损伤修复基因参与POI发生的分子机理，为女性生育力保护提供依据。

Primary ovarian insufficiency (POI), defined as cessation of menstruation before the expected age of menopause, is one of the commonest reproductive endocrine disorders for women of child bearing age. The underlying explanation for POI remains to be elucidated in most cases. The applicant has been engaged in the study of genetic causes of POI over ten years. Progress has been made in identifying causative genes and elucidating mechanism using Sanger sequencing, GWAS, and whole exome sequencing in sporadic and familial patients with POI. She has published 30 papers in peer-reviewed journals, including Am J Hum Genet, Hum Mol Genet, Fertil Steril, and Orphanet J Rare Dis. She was awarded the Author of National Excellent Doctoral Dissertation of China (2009) and Program for New Century Excellent Talents in University (2012). As the project leader, the applicant has undertaken 3 funds of the National Natural Science Foundation of China (81000236, 81270662, and 81471509) and participated in the National Basic Research Program of China (973 program-2012CB944700)..Based on previous data, non-coding RNA, including miR-379-5p, lncRNA1, and lncRNA9 were up-regulated in the granulosa cells of patients with POI. The XRCC6 and PARP1 genes, involved in DNA damage repair pathway, are possible targets for miR-379-5p, lncRNA1, and lncRNA9. It is presumed that dysfunction of XRCC6 and PARP1, regulated by miR-379-5p, lncRNA1, and lncRNA9, participate in the development of POI. The present project will explore the regulatory mechanism of miR-379-5p, lncRNA1, and lncRNA9 on XRCC6 and PARP1 to clarify the underlying mechanism−inability to repair DNA damage−is plausible for POI. Discovering non-coding RNA related with ovarian function will reveal the epigenetic mechanisms contributing to the etiology of POI. Our genetic and functional studies will be helpful for the prevention, intervention and treatment of patients with POI.