MKRN3基因突变失活GnIH/NPFFR1通路导致中枢性性早熟的发病机制研究

中枢性性早熟（CPP）是因下丘脑-垂体-性腺轴（HPG轴）过早激活导致儿童性早熟的疾病，严重危害患儿身心健康。MKRN3基因突变是CPP最常见的遗传病因，其作用机制尚未明确。当前缺少合适的MKRN3基因修饰动物模型，使得临床前治疗研究受限。与小鼠模型相比，家兔发育进程更慢，更适合深入观察CPP发生发展过程和用于治疗研究。申请人前期制备了首例MKRN3基因修饰家兔，并发现MKRN3突变引起家兔促性腺激素抑制激素（GnIH）和其受体NPFFR1表达显著降低。我们推测MKRN3突变后失活或削弱了GnIH通路对HPG轴的重要抑制作用，从而导致CPP。本项目拟从转录调控、转录后调控和蛋白间相互作用等层面，在细胞和个体水平上，深入研究MKRN3对GnIH/NPFFR1通路的作用，并利用家兔模型开展GnIH激动剂治疗性研究。本项目有望进一步揭示MKRN3突变导致CPP的发病机制，为临床治疗提供候选策略。

Central precocious puberty (CPP) is a disease in which children develop precocious puberty due to the premature activation of hypothalamic-pituitary-gonadal axis (HPG axis), which seriously affects the physical and mental health of the children. MKRN3 gene mutation is the most common inherited pathogenic factor of CPP, and its mechanism of action has not been elucidated. Due to the lack of suitable MKRN3 gene-modified animal models, preclinical treatment test is restricted. Compared with the mouse model, the pubertal development process of rabbits is relatively slower, which is more suitable for in-depth observation of the pathogenetic process of CPP and for treatment study. The applicant generated the first case of MKRN3 gene-modified rabbit, and found that MKRN3 mutation caused a significant decrease in the expression of gonadotropin-inhibitory hormone (GnIH) and its receptor NPFFR1. We hypothesized that MKRN3 mutation resulted in CPP due to the weakening of the important inhibitory effect of GnIH on the HPG axis. This project intends to conduct intensive study on the mechanism of MKRN3 on the GnIH/NPFFR1 pathway at the cellular and individual levels from the aspects of transcriptional regulation, post-transcriptional regulation, and protein-protein interactions, and apply rabbit models for GnIH agonist therapeutic research. This project is expected to further reveal the pathogenesis of CPP caused by MKRN3 mutation and provide candidate strategies for clinical therapeutics.