功能性遗传变异调控BARD1/BRCA1泛素化通路的机制及与儿童神经母细胞瘤的关联研究

神经母细胞瘤(NB)是常见儿童颅外恶性肿瘤，恶性度高预后差，机制不清。单核苷酸多态(SNP)与NB发生发展相关，其中包括BARD1 (BRCA1-Associated RING Domain 1)，它与BRCA1组成泛素连接酶在泛素通路发挥作用。前期我们鉴定出BARD1基因11个SNP与NB易感性相关（病例-对照500-1000）。因此本项目拟筛查BARD1/BRCA1通路与NB易感相关SNP; 用荧光素酶报告基因实验、EMSA等研究位于UTR区SNP对基因转录调控作用；利用Co-IP、poly-ubiquitination、MTT等研究编码区SNP对 BARD1/BRCA1蛋白相互作用及其泛素连接酶的影响；病例-对照(1000-2000)研究验证功能性SNP与NB关联性，以期阐明BARD1/BRCA1泛素通路功能性多态与NB发生发展的关系及其分子机制，为确立NB诊治预后指标提供实验依据。

Neuroblastoma (NB) is the most common extracranial solid pediatric tumor, with high malignancy and poor prognosis. BARD1 (BRCA1-Associated RING Domain 1), together with BRCA1 (Breast Cancer 1), comprise an E3 ubiquitin ligase, playing important roles in Ubiquitin proteasome pathway. BARD1/BRCA1 pathway is related to the development of a variety of tumors, including NB. The genetic basis and mechanisms of NB pathogenesis remains largely unclear. In the NB case-control (500-1000) study, we identified several single nucleotide polymorphisms (SNP) of BARD1 gene associated with NB. Based on those results, in this project, we propose to study the role of SNPs in transcriptional and functional regulation in genes of BARD1/BRCA1 pathway, with the goal of delineating the relationship between BARD1/BRCA1 gene polymorphisms and NB susceptibility in children. The results of this study will help us understand the molecular mechanism of NB progression; explore the role of BARD1/BRCA1 gene polymorphisms in tumor invasion and metastasis in NB children, and provide experimental evidence for establishing clinical prognostic indicators.