基于miRNA靶基因调控区重测序的脑出血继发血肿扩大的遗传研究

Hematoma enlargement (HE) after intracerebral hemorrhage (ICH), a main cause of neurological deterioration, as well as a significant increase in morbidity and mortality, attracts much attention worldwide recently. Although progression in imaging pre-warning of HE after ICH is made, its molecular mechanism still remains unclear. As a complex genetic disorder, HE is greatly attributed to genetic predisposition, by the abnormal function or expression of the genes and regulation of microRNA (miRNA) in gene expression. In our preliminary study, the specific expressions of circulating miRNAs were early pre-warning indexes in HE after ICH. We plan to apply candidate gene associated approach to analyze single-nucleotide polymorphisms (SNPs) information in different samples by establishment of DNA library via chip-sequence capture technologies and resequencing of DNA via second-generation sequencing technology, in order to explore miRNA regulation in different individuals and identify susceptibility genes from candidate genes in regulatory regions associated with HE after ICH. Ultimately we aim to determine new genetic markers of HE after ICH in Han and providing the basis for pre-warning and intervention of HE.

脑出血（ICH）后血肿扩大（HE）是患者早期神经功能恶化、致残率、致死率显著增高的主要原因,近年来引起全球关注。ICH继发HE的影像学预警探索取得了一定进展，但其发生的分子基础仍未明确。作为复杂基因病，HE发生与基因功能或表达水平异常相关，miRNA参与基因表达调控，遗传易感性是发病重要因素。我们前期发现ICH继发HE患者外周血存在一系列miRNA特异性表达，可以作为HE早期预警指标。本项目拟应用候选基因关联分析方法，采用序列捕获芯片技术抓取不同样本组样本建立DNA文库，应用第二代测序技术对样本进行重测序，得到这些区域的SNP信息进行分组间关联分析，以探索miRNA在不同个体间调控效力不同的机制，在miRNAs候选调控靶基因区域寻找ICH继发HE易感基因或位点，最终确定汉族ICH人群继发HE新遗传分子靶标，为HE的早期预警和干预提供依据。

脑出血（ICH）后血肿扩大（HE）是患者早期神经功能恶化、致残率、致死率显著增高的主要原因,近年来引起全球关注。ICH继发HE的影像学预警探索取得了一定进展，但其发生的分子基础仍未明确。作为复杂基因病，HE发生与基因功能或表达水平异常相关，miRNA参与基因表达调控。我们的研究旨在了解miRNA及基因调控在ICH血肿扩大中的机制作用。研究结果表明：ICH继发HE患者外周血存在一系列miRNA特异性表达，有显著性差异表达的miRNA共18个，表达上调的10个，表达下调的8个。经实验验证miRNA-4687和miRNA-362通过负性调控CYLD因子，促使NF-κB信号通路激活,可能是患者血肿扩大的关键因素。