Computational- and experimental- driven discovery of splicing regulation and circRNA function

计算和实验驱动的剪接调控和 circRNA 功能发现

• 批准号: 10565918
• 负责人: Julia Salzman
• 金额: $ 39.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565918
• 关键词: Alternative Splicing; Biological; Biological Markers; Biology; Cells; Complex; Coupled; DNA; DNA Sequence; Data; Development; Disease; Drug Targeting; Eukaryota; Evolution; Generations; Genes; Genetic; Genetic Transcription; Genome; Knowledge; Nucleic Acids; Organism; Output; Pathogenicity; Process; Processed Genes; Protein Isoforms; Proteins; RNA; RNA Splicing; Regulation; Research; Statistical Data Interpretation; Untranslated RNA; Validation; Variant; cell type; digital; disease diagnostic; genetic variant; insight; novel; precision medicine; public health relevance; therapeutic target

Project Summary/Abstract Cells and organisms, from simple to complex, carry the same genetic DNA sequence organized into genes. Multicellular eukaryotes transcribe and process genes into RNA isoforms through a process called alternative splicing. Alternative splicing is developmentally and cell-type specifically regulated. It is foundational to how higher organisms’ genomes are decoded. Yet, critical and fundamental questions regarding its regulation and the function of its output remain unanswered. For example, circRNA being a ubiquitous product of alternative splicing was only discovered in 2012, and its regulation and function remains enigmatic. circRNAs’ discovery revealed a larger critical knowledge gap in the field for “what, how and why” genes are alternatively spliced. What RNA splice variants are expressed, how splicing is regulated and which spliced RNAs have essential functions? Answering these questions is critical for predicting which of myriad genetic variants cause disease and why they do so. Answers will also enable a new generation of digital nucleic acid biomarkers and diagnostics for disease, drug targets for correcting dysregulated splicing and identification of pathogenic protein- or non-coding products (respectively) as well as fundamental basic scientific insight into evolution and function of eukaryotic genomes. The proposed research will couple novel statistical analyses of -omics data by taking an unbiased approach and including biological features that are understudied or un-annotated. Predictions will be coupled with incisive experimental validation to reveal new principles of how RNAs, including circRNAs, are spliced and how they function. This research potentiates significant new discoveries in why alternative splicing exists and how this understanding can be used for precision medicine.

项目摘要/摘要 细胞和生物体，从简单到复杂，携带着组织成基因的相同的基因DNA序列。 多细胞真核生物通过一种称为替代的过程将基因转录并加工成rna亚型。 拼接。选择性剪接受发育和细胞类型的特殊调控。它是如何 高等生物的基因组被破译。然而，关于其监管和监管的关键和根本问题 其产出的作用仍未得到回答。例如，CircRNA是替代的无处不在的产物 剪接是2012年才被发现的，它的调控和功能仍然是个谜。CircRNAs的发现 揭示了在“什么、如何和为什么”基因交替拼接的领域中更大的关键知识缺口。 表达了哪些RNA剪接变体，剪接是如何调控的，以及哪些剪接RNA具有必不可少的 功能？回答这些问题对于预测无数基因变异中哪些会导致疾病至关重要 以及他们这样做的原因。答案还将使新一代数字核酸生物标记物和 疾病的诊断，纠正异常剪接的药物靶点和病原体的鉴定 分别是蛋白质或非编码产品，以及对进化和 真核基因组的功能。拟议的研究将结合对组学数据的新的统计分析，通过 采取不偏不倚的方法，包括未被研究或未加注释的生物学特征。 预测将与精辟的实验验证相结合，以揭示RNA如何， 包括CircRNA，都是拼接的，以及它们是如何发挥作用的。这项研究加强了重大的新发现 为什么会存在选择性剪接，以及如何将这种理解用于精确医学。