Non-coding RNAs and their mechanisms and functions

非编码RNA及其机制和功能

• 批准号: 10594052
• 负责人: Richard W. CARTHEW
• 金额: $ 63.45万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594052
• 关键词: Affect; Area; Award; Biochemical Reaction; Biological; Biological Process; Biophysics; Cell Differentiation process; Cells; Cellular Metabolic Process; Data Set; Development; Developmental Biology; Developmental Process; Drosophila genus; Energy Metabolism; Flushing; Functional disorder; Future; Gene Activation; Gene Expression; Gene Expression Regulation; Genetic; Goals; Human; Human Genome; Life; Link; Mammals; Metabolism; Modeling; Molecular; Morphogenesis; Nature; Organism; Pattern; Process; Property; RNA; Regulation; Regulator Genes; Reiterated Genes; Research; System; Tissue Engineering; Tissues; Untranslated RNA; Work; experience; experimental study; flexibility; fly; high dimensionality; human disease; intercellular communication; mathematical model; mechanical force; model organism; programs

PROJECT SUMMARY My research is focused on two different areas of gene regulation within the context of developmental biology. One area concerns the molecular mechanisms and functions of non-coding RNAs. Long non-coding RNAs (lncRNAs) are the most ubiquitous of non-coding RNAs, with tens of thousands annotated in the human genome. Yet, they are also the most poorly understood non-coding RNA, as only a small fraction of annotated lncRNAs have been characterized at a mechanistic level. Therefore, it is important to obtain a basic understanding of how these RNAs work, how they are regulated, and what broad biological functions they have. We focus on studying these questions in the model organism Drosophila because the mechanisms and regulation thus far discovered in flies are highly similar to humans. The rich genetics of Drosophila enable functional experiments that would not be possible in mammals. This award will support our efforts to discover new principles of lncRNA regulation and flush out necessary detailed information about previous discoveries. The second area concerns the interplay between gene regulatory programs and extrinsic inputs such as cell metabolism, cell morphogenesis, and physically-based processes. We combine mathematical modeling and quantitative experiments in Drosophila to define the links between these extrinsic inputs and gene regulation. We generate substantial technical advances in quantitative approaches including (1) new high dimensional biological datasets across spatial (cellular to organism) and temporal scales, (2) new conceptual models of diverse developmental processes, and (3) mathematical models that describe developmental emergence. Future directions include understanding whether redundant gene activation is a common feature of life because it affords greater flexibility to regulatory programs to faithfully couple with cellular energy metabolism. Another direction concerns the inherent stochasticity in biochemical reactions and how that affects the fidelity of cell differentiation and patterning. Another future direction is to adapt our proven approaches to explore how mechanical forces experienced by cells within tissues cause changes in their gene expression programs. Understanding the biophysical nature of tissues will have great benefit for tissue engineering.

项目总结 我的研究集中在发育生物学背景下的两个不同的基因调控领域。 其中一个领域涉及非编码RNA的分子机制和功能。长的非编码RNA (LncRNAs)是最普遍的非编码RNA，在人类中有数万个注释 基因组。然而，它们也是最鲜为人知的非编码RNA，因为只有一小部分带注释的 LncRNAs已被描述在机械学水平上。因此，重要的是获得基本的 了解这些RNA是如何工作的，它们是如何被调控的，以及它们具有哪些广泛的生物学功能 有。我们专注于在模式生物果蝇中研究这些问题，因为 到目前为止，在苍蝇身上发现的规则与人类高度相似。果蝇丰富的遗传学使 在哺乳动物身上不可能进行的功能实验。这一奖项将支持我们发现 LncRNA调控的新原理，并提供关于以前发现的必要的详细信息。 第二个领域涉及基因调控程序和细胞等外部输入之间的相互作用 新陈代谢、细胞形态发生和基于物理的过程。我们将数学建模和 在果蝇中进行定量实验，以确定这些外部输入和基因调控之间的联系。 我们在定量方法方面取得了实质性的技术进步，包括(1)新的高维 跨越空间(细胞到生物体)和时间尺度的生物数据集，(2)新的概念模型 不同的发展过程；(3)描述发展涌现的数学模型。 未来的方向包括了解多余的基因激活是否是生命的共同特征 因为它为调节程序提供了更大的灵活性，使其与细胞能量代谢忠实地结合在一起。 另一个方向涉及生化反应中固有的随机性以及它如何影响保真度 细胞分化和图案化。另一个未来的方向是采用我们经过验证的方法来探索如何 细胞在组织中所经历的机械力会导致其基因表达程序的变化。 了解组织的生物物理性质将对组织工程有很大的帮助。