LncRNA-HIP促进海马神经发生改善宫内生长受限子代认知障碍的机制研究

子宫内不良环境常会通过改变表观遗传修饰引发胎儿宫内生长受限（IUGR），继而导致海马体积缩小并增加子代认知障碍风险。长链非编码RNA（lncRNA）在此过程中的作用研究尚未见报道。我们前期发现IUGR小鼠海马神经干细胞增殖能力下降，导致神经发生受抑制且认知功能受损。高通量测序筛选获得IUGR小鼠海马中显著下调的lncRNA-HIP，在体内外过表达皆能促进IUGR小鼠海马神经干细胞增殖，且可能受Tet1调控，并靶向Notch信号通路。本项目拟利用CRISPR/Cas9、RIP等技术，阐明调控IUGR小鼠海马lncRNA-HIP表达，及lncRNA-HIP调控海马神经干细胞增殖的上下游机制；探索lncRNA-HIP能否改善IUGR小鼠认知障碍；考察人源lncRNA-HIP的功能和机制的保守性。本项目将有助于理解胎源性神经疾病的lncRNA调控机制，为IUGR子代认知障碍的干预治疗提供依据。

The negative intrauterine environment often cause intrauterine growth restriction (IUGR), which in turn leads to reduced hippocampal size and increased risk of cognitive impairment in offspring. Epigenetic modifications play important roles in IUGR related diseases, but the role of long non-coding RNA (lncRNA) in this process has not been reported. In our previous study, IUGR mice show decreased hippocampal neural stem cell proliferation, leading to inhibited neurogenesis and impaired recognition. High-throughput sequencing analysis revealed that the expression level of lncRNA-HIP is significantly reduced in the hippocampus of IUGR mice. Overexpression of lncRNA-HIP can promote the proliferation of hippocampal neural stem cells in IUGR mice in vivo and in vitro. We discovered that lncRNA-HIP may be regulated by Tet1 and target Notch signaling pathway in the hippocampus of IUGR mice. Using CRISPR/Cas9, RIP and other technologies, this project will elucidate the mechanisms of regulating the expression of lncRNA-HIP in the hippocampus of IUGR mice, and lncRNA-HIP regulating the proliferation of hippocampal neural stem cells. Furthermore, this project will explore whether lncRNA-HIP can improve cognitive impairment in IUGR mice, and investigate the conservation of human lncRNA-HIP function and mechanism. Our results will not only help people to understand the lncRNA regulatory mechanism underlying the fetal original neurological diseases, but also provide the theoretical basis for the intervention treatment of cognitive impairment in IUGR offspring.