LOC100909675对脊髓损伤中星形胶质细胞功能转换的机制研究

脊髓损伤（SCI）后星形胶质细胞的活化，胶质瘢痕形成是阻碍神经再生的重要因素。长链非编码（Lnc）RNA是一种新型表观遗传调节因子，参与了损伤后胶质细胞活化和胶质瘢痕形成。申请人前期研究发现一个脊髓损伤后显著上调表达的LncRNA-LOC100909675，体外敲降其表达能够改变脊髓星形胶质细胞的增殖、神经毒性（A1）、神经营养（A2）等功能表型。该分子在细胞核内表达，生物信息分析提示该分子能够与含zf_C2H2结构域的转录因子结合并调节相关基因表达。本课题拟解析LOC100909675如何与zf_C2H2结构域相互作用，并阐明脊髓损伤不同阶段LOC100909675对含zf_C2H2结构域的Cdk1、Cdc20等周期相关基因，Gbp2等A1型星胶基因，Cd109等A2型星胶基因的转录调控，探讨该分子与胶质活化与功能转换的作用关系，为LncRNA在神经再生的机制研究增加新内容。

The processes of astrocytes activation and glial scar limit nerve regeneration during spinal cord injury, and the long non-coding (Lnc) RNA is involved to affect these processes as a novel epigenetic regulator. Our previous study found that a LncRNA molecule, LOC100909675 significantly up-regulates after spinal cord injury, and depleting its expression from the astrocytes of rat spinal cords could dramatically inhibit the cell proliferation, and interestingly, the conditional medium derived from LOC100909675 depleted cultured astrocytes remarkably increases the axonal length. We analyzed the RNA expression profiles of astrocytes depleted LOC100909675 and found the significant differential genes switched to neuroprotection (A2 type) astrocytes from neurotoxic (A1 type), and GO and KEGG analysis showed they significantly clustered into a kind of genes, whose transcription factors containing zf_C2H2 domain. Based on LncRNA-LOC100909675 molecules localize in nuclei, we suggest that LOC100909675 could bind to the specific zf_C2H2 domain and then regulate transcription of the target genes. Therefore, in this proposal, we will clarify that, how LOC100909675 interacts with zf_C2H2 domain; when LOC100909675 regulates the target genes which upstream containing zf_C2H2 domain binding sites, e.g. Cdk1, Cdc20 (cell cycle related genes), Gbp2 (a marker gene of A1 type) and Cd109 (a marker gene of A2 type) during spinal cord injury, and finally what a kind of the pathway between LOC100909675 and astrocytes activation or functional transformation. This study will provide a new interpretation of the LncRNA’s character in nerve regeneration.