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.

项目总结/摘要 该项目研究非- 并研究抑制其在疾病中功能的新方法。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， 患者预后影响RNA结构和蛋白结合。它旨在开发工程化的 蛋白质和肽模拟物抑制人类癌症中的ncRNA错误功能。 它的前提是通过以下途径提供对ncRNA的分子机制的见解： 结构分析和结构-功能关系的建立是生物学研究的重要内容之一。 目前分子结构生物学中最重要的悬而未决的问题，因为 这一发现所造成的知识上的巨大差距， 转录物被积极地转录。此外，广泛发生的功能性 ncRNA的遗传变异，以及基因突变或错误表达的相关性， ncRNA与患者疾病结局的关系强调了这些基因的生物医学重要性。 并揭示其潜在的治疗价值。分子的洞察力是必要的， 充分了解它们的生物学功能，构建关于失调如何， 突变或转录后修饰导致人类疾病，鉴定和 验证分子靶点并发现新的药物干预化学。 这些广泛的目标将通过多规模的方法来实现， ncRNA的结构，包括对结构域的高分辨率研究， 它们具有特定的功能，以及它们与蛋白质和microRNA的相互作用。项目 还将进一步开发工程蛋白和肽模拟物， 参与恶性转化的ncRNA的靶向功能结构域。合作 与癌症和发育生物学家一起，我们将在原代细胞系中进行实验， 和生物模型来与我们的生物化学，生物物理和结构研究相平行， 并获得活性和作用机制的细胞和有机体验证， 新的抑制剂