RNA-based mechanisms in nuclear steps of gene expression

基因表达核步骤中基于 RNA 的机制

• 批准号: 9070879
• 负责人: DAVID A BROW
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070879
• 关键词: Apraxias; Ataxia; Biotechnology; Blindness; Cells; Cerebellar Ataxia; Cerebellum; DNA; Defect; Diagnosis; Disease; Due Process; Gene Expression; Genetic Transcription; Heart; Human; Inherited; Knowledge; Lead; Molecular; Muscle Weakness; Mutation; Nuclear; Pathway interactions; Process; RNA; RNA Polymerase II; RNA Splicing; RNA-Protein Interaction; Retinal Degeneration; Retinitis Pigmentosa; Small Nuclear Ribonucleoproteins; Tissues; accurate diagnosis; base; improved; mRNA Precursor; novel therapeutic intervention; outcome forecast; public health relevance; synthetic biology; transcription termination

 DESCRIPTION (provided by applicant): RNA-RNA and RNA-protein interactions lie at the heart of essential steps of the eukaryotic gene expression pathway. Defects in these processes due to inherited mutations can result in degeneration of the retina, cerebellum, and other tissues. The proposed studies will result in a better understanding of RNA-based mechanisms of gene expression in both the normal and disease states. In particular, we will determine the molecular mechanism for U4/U6.U5 tri-snRNP assembly and activation in pre-mRNA splicing, and for Sen1- dependent termination of transcription by RNA polymerase II. Inherited defects in the first process can lead to autosomal dominant retinitis pigmentosa (adRP), which results in progressive blindness, and in the second process can lead to ataxia ocular apraxia type 2 (AOA2), which results in progressive muscle weakness (cerebellar ataxia). In neither case is the relationship between the molecular defect and the disease understood. Better knowledge of the molecular mechanisms of pre-mRNA splicing and transcription termination should lead to more accurate diagnosis and prognosis of these and other diseases, and may ultimately result in new therapeutic approaches. Furthermore, the proposed studies will illuminate basic mechanisms of eukaryotic gene expression that can be exploited for synthetic biology and biotechnology.

 描述（由申请人提供）：RNA-RNA和RNA-蛋白质相互作用是真核基因表达途径基本步骤的核心。由于遗传突变导致的这些过程中的缺陷可导致视网膜、小脑和其他组织的变性。拟议的研究将导致更好地理解在正常和疾病状态下基于RNA的基因表达机制。特别是，我们将确定U4/U6.U5三-snRNP组装和激活前体mRNA剪接的分子机制，以及RNA聚合酶II依赖于Sen 1的转录终止。在第一个过程中的遗传缺陷可导致常染色体显性视网膜色素变性（adRP），其导致进行性失明，并且在第二个过程中可导致共济失调眼失用症2型（AOA 2），其导致进行性肌无力（小脑共济失调）。在这两种情况下，分子缺陷和疾病之间的关系都不清楚。更好地了解前体mRNA剪接和转录终止的分子机制将导致这些和其他疾病的更准确的诊断和预后，并可能最终导致新的治疗方法。此外，拟议的研究将阐明可用于合成生物学和生物技术的真核基因表达的基本机制。