REGULATION OF ALTERNATIVE PRE-MRNA PROCESSING BY SMALL NUCLEOLAR RNAS

小核仁 RNA 对替代性前 mRNA 加工的调节

• 批准号: 7720904
• 负责人: Stefan Stamm
• 金额: $ 7.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720904
• 关键词: Alternative Splicing; Computer Retrieval of Information on Scientific Projects Database; Defect; Drug Delivery Systems; Funding; Gene Targeting; Genes; Genetic; Grant; Heterogeneous Nuclear RNA; Individual; Institution; Knowledge; Life; Masks; Molecular; Obesity; Pattern; Prader-Willi Syndrome; Process; Protein Overexpression; RNA Splicing; Regulation; Regulatory Element; Research; Research Personnel; Resources; Role; Site; Small Nucleolar RNA; Small RNA; Source; Textbooks; United States National Institutes of Health; Work; base; innovation; mRNA Precursor; novel

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该项目的目标是确定小核仁 RNA (snoRNA) 表达的缺失如何导致普瑞德-威利综合征，这是危及生命的肥胖最常见的遗传原因。我们将确定哪些选择性剪接模式受到普瑞德-威利综合征个体中缺失的 snoRNA 的影响，并阐明其中一种 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 通过掩盖前 mRNA 上的剪接调节元件来调节选择性剪接。因此，这些 snoRNA 通过改变其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，这些 snoRNA 调控的基因代表了治疗普瑞德威利综合征的药物靶点。我们使用 snoRNA 表达构建体的过表达来验证生物信息学预测的靶基因。这项工作具有创新性，因为它展示了 snoRNA 在调节选择性前 mRNA 剪接中的全新作用。它很可能会改变目前 snoRNA 只调节非 mRNA 的“教科书知识”。这项研究意义重大，因为它将展示 snoRNA 的新作用，识别 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。