REGULATION OF ALTERNATIVE PRE-MRNA PROCESSING BY SMALL NUCLEOLAR RNAS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的目的是确定小核仁RNA（snoRNA）表达的缺失如何导致Prader-Willi综合征，这是危及生命的肥胖症最常见的遗传原因。我们将确定哪些选择性剪接模式的影响与Prader-Willi综合征的个体缺失的snoRNA，并阐明这些snoRNA，HBII-52，影响选择性剪接模式的分子基础。核心假设是Prader-Willi综合征个体中缺失的snoRNA通过掩蔽前mRNA上的剪接调节元件来调节选择性剪接。因此，这些snoRNA通过改变它们的选择性剪接模式来调节许多基因的表达。这项研究的基本原理是，由这些snoRNA调控的基因代表了治疗Prader-Willi综合征的药物靶点。我们使用过表达snoRNA的构建体来验证生物信息学预测的靶基因。这项工作是创新的，因为它显示了snoRNA在调节选择性前mRNA剪接中的全新作用。它可能会改变目前的“教科书知识”，snoRNA只调节非mRNA。这项研究具有重要意义，因为它将显示snoRNA的新作用，确定Prader-Willi综合征的分子缺陷，并有助于预测小RNA对剪接位点选择的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of the project is to determine how the loss of small nucleolar RNA (snoRNA) expression contributes to the Prader-Willi syndrome, the most frequent genetic cause for life-threatening obesity. We will determine which alternative splicing patterns are influenced by the snoRNAs missing in individuals with Prader-Willi syndrome and elucidate the molecular basis by which one of these snoRNAs, HBII-52, influences alternative splicing patterns. The central hypothesis is that snoRNAs missing in individuals with Prader- Willi syndrome regulate alternative splicing by masking splicing regulatory elements on pre-mRNAs. Thus these snoRNAs regulate expression of numerous genes by changing their alternative splicing patterns. The rationale for the proposed research is that the genes regulated by these snoRNAs represent drug targets for treatment of the Prader-Willi syndrome. We use overexpression of snoRNA-expressing constructs to validate bioinformatically predicted target genes. The proposed work is innovative, because it shows a complete new role for snoRNAs in the regulation of alternative pre-mRNA splicing. It may well change the current 'textbook knowledge' that snoRNAs only regulate non-mRNAs. The proposed research is significant because it would show a novel role of snoRNAs, identify the molecular defects in Prader-Willi syndrome and help to predict the influence of small RNAs on splice site selection.