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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的目标是确定小核仁RNA(SnoRNA)表达缺失如何导致Prader-Willi综合征，这是威胁生命的肥胖症最常见的遗传原因。我们将确定Prader-Willi综合征患者中缺失的snoRNAs会影响哪些选择性剪接模式，并阐明其中一个snoRNAs HBII-52影响选择性剪接模式的分子基础。中心假说是，Prader-Willi综合征患者体内缺失的snoRNAs通过掩盖前mRNAs上的剪接调控元件来调节选择性剪接。因此，这些snoRNAs通过改变它们的选择性剪接模式来调节许多基因的表达。这项拟议研究的基本原理是，受这些snoRNAs调控的基因代表着治疗Prader-Willi综合征的药物靶点。我们使用snoRNA表达载体的过表达来验证生物信息学预测的靶基因。这项拟议的工作是创新的，因为它显示了snoRNAs在调节替代前mRNA剪接中的全新角色。这很可能改变目前snoRNAs只调控非mRNAs的“教科书知识”。这项研究具有重要意义，因为它将揭示snoRNAs的新作用，识别Prader-Willi综合征的分子缺陷，并有助于预测小RNAs对剪接位点选择的影响。