长链非编码RNA lncARER1调控TIMP3基因在反复胚胎种植失败中的作用及机制研究

Recurrent implantation failure (RIF) is a condition in which infertile couples fail to achieve a clinical pregnancy following repeated transfers with high quality embryos during in vitro fertilization (IVF). Although the underlying pathogenesis of RIF remains poorly characterized, it is increasingly apparent that this heterogeneous disease is coupled to aberrant endometrial receptivity. To date, accumulated evidence has underlined the importance of the protein-encoding genes in a functioning and receptive endometrium. However, the regulation mechanism of distorted endometrial receptivity in RIF has been remained enigmatic. Therefore, it is necessary to explore the pathogenesis of endometrial dysfunction in RIF from other viewpoints. Our previous researches exhibited that long non-coding RNA (lncRNA) lncARER1 and its predicted target gene TIMP3 were elevated in endometrial tissues from RIF patients. Forced expression of lncARER1 significantly promoted human endometrial stromal cells proliferation and decidualization. Meanwhile, lncARER1 overexpression markedly up-regulated the expression of TIMP3 gene in stromal cells. It is presumed that dysregulated lncARER1 may be responsible for abnormal endometrial receptivity and subsequent implantation failure in RIF via disordering TIMP3 gene and its related signalling pathway. Based on the previous results, we will investigate the influence of lncARER1 in endometrial receptivity and further reveal the underlying mechanism of lncARER1 by regulating TIMP3 and its related signalling pathway in RIF. Our findings will provide new insights into epigenetic pathogenesis in aberrant endometrial receptivity for RIF and strengthen the concept that modulating disordered lncRNAs might make for bettering endometrial receptivity and implantation rates in RIF patients.

子宫内膜容受性异常是导致反复胚胎种植失败（RIF）的主要原因，目前其建立的确切机制尚不清楚，且既往研究多关注蛋白编码基因的功能和机制研究，尚无长链非编码RNA在RIF子宫内膜容受性异常这一病理过程中的作用及机制报道。申请人前期研究发现lncARER1及其预测靶基因TIMP3在RIF患者着床期子宫内膜组织中表达显著上调，且过表达lncARER1促进基质细胞增殖和蜕膜化，同时显著上调TIMP3基因表达，提示lncARER1可能通过调控TIMP3基因及相关通路干扰子宫内膜容受性建立过程，影响胚胎植入，参与RIF发生。申请人拟在前期研究基础上，继续深入研究lncARER1对子宫内膜容受性建立过程的影响，阐明lncARER1调控TIMP3基因及相关通路的作用和机制，从而揭示lncARER1与RIF发生发展的相关性，为RIF表观遗传学病因研究提供线索。

反复胚胎种植失败（recurrent implantation failure，RIF）病因高度异质，造成了优质胚胎资源的极大浪费，是限制体外助孕成功率进一步提高的瓶颈问题。本项目研究发现长链非编码RNA（long non-coding RNA，lncRNA）lncARER1的异常表达不影响内膜容受性建立，提示其不参与胚胎种植失败的发生。环状RNA（circular RNA，circRNA）作为非编码RNA研究的热点领域，其在人子宫内膜容受性建立及胚胎植入过程中的作用鲜有报道。我们重点围绕环状circRNA在RIF患者内膜组织中的表达、作用及机制进行研究，继续从表观遗传学角度解析RIF发生发展的分子机理；同时关注体外助孕妊娠结局的影响因素分析，优化胚胎移植策略。研究发现circSTK40/HSP90/AKT/FOXO1、circFAM120A/miR-29/ABHD5通路缺陷导致子宫内膜容受性异常、参与 RIF 发生进展的分子机理，从表观遗传学角度扩展RIF的病因机制研究，为 RIF临床精准诊疗提供了研究基础和新靶点。同时揭示囊胚长期玻璃化冷冻保存对妊娠及新生儿结局的影响，为优化胚胎移植策略、提高体外助孕成功率提供重要参考依据。