ncRNA: Structure, Interactions and Inhibition

ncRNA：结构、相互作用和抑制

• 批准号: 10391314
• 负责人: Gabriele Varani
• 金额: $ 63.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391314
• 关键词: Affect; Animal Model; Binding Proteins; Biochemical; Biological Process; Biophysics; Cancer Patient; Cell Line; Cell model; Chemicals; Chemistry; Collaborations; Development; Disease; Disease Outcome; Enzymes; Epigenetic Process; Genetic Transcription; Genetic Variation; Genome; Goals; Human; Intervention; Investigation; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; MicroRNAs; Modification; Molecular; Molecular Target; Mutation; Patients; Pharmacology; Protein Engineering; Proteins; RNA; RNA-Binding Proteins; Research Project Grants; Resolution; Structure; Structure-Activity Relationship; Therapeutic; Transcript; Untranslated RNA; Validation; experimental study; human disease; inhibitor; insight; novel strategies; patient prognosis; peptidomimetics; structural biology; tool; tumor progression

Project Summary/Abstract This project studies the structural principles underlying the biological function of non- coding RNAs and investigates new approaches to inhibiting their function in disease. It studies how these transcripts fold; how they recognize other RNAs, RNA-binding proteins and epigenetic enzymes; how functional SNPs correlated with cancer progression or patient prognosis affect RNA structure and protein binding. It aims to develop engineered proteins and peptide mimetics to inhibit ncRNA misfunction in human cancers. Its premise is that providing molecular mechanistic insight on ncRNA through structure analysis and the establishment of structure-function relationships is one of the most important current outstanding questions in molecular structural biology, because of the enormous gap in knowledge created by the discovery that hundreds of thousands of transcripts are actively transcribed. Furthermore, the widespread occurrence of functional genetic variation in ncRNAs, and the association of mutation or mis-expression of ncRNAs with disease outcome in patients underscore the biomedical importance of these transcripts and reveal their potential therapeutic value. Molecular insight is necessary to fully understand their biological function, frame hypotheses on how misregulation, mutation or post-transcriptional modification causally lead to human disease, identify and validate molecular targets and discover new chemistry for pharmacological intervention. These broad goals will be pursued through a multi-scale approach to establishing the structure of ncRNAs, including the high resolution investigation of domains where specific functions reside, and of their interaction with proteins and microRNAs. The project will also pursue the further development of engineered proteins and peptide mimetics that target functional domains of ncRNAs involved in malignant transformation. In collaboration with cancer and developmental biologists, we will conduct experiments in primary cell lines and model organisms to parallel our biochemical, biophysical and structural investigations, and obtain cellular and organismal validation of the activity and mechanism of action of new inhibitors.

项目概要/摘要 该项目研究非生物功能的结构原理 编码 RNA 并研究抑制其在疾病中的功能的新方法。它 研究这些转录本如何折叠；它们如何识别其他 RNA、RNA 结合蛋白 和表观遗传酶；功能性 SNP 如何与癌症进展相关或 患者预后影响RNA结构和蛋白质结合。其目的是开发工程 蛋白质和肽模拟物可抑制人类癌症中的 ncRNA 功能障碍。 其前提是通过 结构分析和结构-功能关系的建立是其中之一 分子结构生物学中当前最重要的悬而未决的问题，因为 数十万的人的发现所造成的巨大知识鸿沟 转录本是主动转录的。此外，功能性症状的广泛发生 ncRNA 的遗传变异，以及突变或错误表达的关联 与患者疾病结果相关的 ncRNA 强调了这些的生物医学重要性 转录本并揭示其潜在的治疗价值。分子洞察力是必要的 充分了解它们的生物学功能，提出关于如何失调的假设， 突变或转录后修饰会导致人类疾病，识别和 验证分子靶标并发现用于药理学干预的新化学。 这些广泛的目标将通过多尺度的方法来实现 ncRNA 的结构，包括对以下结构域进行高分辨率研究 特定功能及其与蛋白质和 microRNA 的相互作用。项目 还将进一步开发工程蛋白质和肽模拟物 参与恶性转化的 ncRNA 的靶功能域。合作中 我们将与癌症和发育生物学家一起在原代细胞系中进行实验 和模型生物体以平行于我们的生物化学、生物物理和结构研究， 并获得其活性和作用机制的细胞和组织验证 新的抑制剂。