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.

项目概要 我的研究重点是发育生物学背景下基因调控的两个不同领域。 其中一个领域涉及非编码 RNA 的分子机制和功能。长非编码RNA (lncRNA) 是最普遍存在的非编码 RNA，在人类中有数以万计的注释 基因组。然而，它们也是人们最了解的非编码 RNA，因为只有一小部分带注释的 RNA lncRNA 已在机制水平上得到表征。因此，获得基本的 了解这些 RNA 的工作原理、它们的调节方式以及它们的广泛生物学功能 有。我们专注于在模式生物果蝇中研究这些问题，因为其机制和 迄今为止在果蝇中发现的调节与人类高度相似。果蝇丰富的遗传学使 在哺乳动物中不可能进行的功能实验。该奖项将支持我们努力发现 lncRNA 调控的新原理，并清除有关先前发现的必要详细信息。 第二个领域涉及基因调控程序与细胞等外在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。我们将数学建模与 在果蝇中进行定量实验，以确定这些外在输入与基因调控之间的联系。 我们在定量方法方面取得了重大技术进步，包括（1）新的高维 跨空间（细胞到有机体）和时间尺度的生物数据集，（2）新的概念模型 不同的发育过程，以及（3）描述发育出现的数学模型。 未来的方向包括了解冗余基因激活是否是生命的共同特征 因为它为监管程序提供了更大的灵活性，以忠实地与细胞能量代谢结合。 另一个方向涉及生化反应固有的随机性及其如何影响保真度 细胞分化和模式化。另一个未来的方向是调整我们行之有效的方法来探索如何 组织内细胞所经历的机械力会导致其基因表达程序发生变化。 了解组织的生物物理性质将对组织工程大有裨益。