Non-coding RNAs and their mechanisms and functions

非编码RNA及其机制和功能

• 批准号: 9894810
• 负责人: Richard W. CARTHEW
• 金额: $ 59.82万
• 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 2021-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894810
• 关键词: Animal Model; Area; Attenuated; Award; Biogenesis; Biological Process; Biology; Biophysics; Bypass; Cells; Characteristics; Drosophila genus; Functional disorder; Future; Gene Expression; Genetic; Genetic Transcription; Genomics; Goals; Human; Infection; Link; Mammals; Mediating; MicroRNAs; Molecular; Morphology; Nature; Noise; Nonesterified Fatty Acids; Nuclear; Pathway interactions; Play; Proteins; RNA; RNA Precursors; RNA Processing; Regulation; Regulator Genes; Repression; Research; Shapes; Signal Transduction; Small Interfering RNA; Small RNA; Source; Stress; Tissue Engineering; Tissues; Transforming Growth Factor beta; Translations; Untranslated RNA; Virus; Work; cancer cell; experience; experimental study; extracellular; fly; human disease; interest; mathematical model; mechanical force; programs; protein expression; public health relevance

 DESCRIPTION (provided by applicant): My research is focused on two different areas of biology. The area to which most of our effort is devoted concerns the molecular mechanisms and functions of small non-coding RNAs. Two classes of small RNAs interest us: microRNAs (miRNAs) and short interfering RNAs (siRNAs). Both are generated by Dicer processing of RNA precursors and both associate with Argonaute proteins to repress post-transcriptional gene expression. Both classes of RNAs have enormous implications for human disease, both in causing it and potentially treating it. Therefore, it is important to obtain a basic understanding f 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 small RNA regulation and flesh out necessary detailed information about previous discoveries. For example, we found extracellular signals to regulate the biogenesis steps and effector steps of the miRNA pathway. Free fatty acid signaling attenuates miRNA-mediated repression whereas TGFβ signaling activates nuclear processing of miRNA precursor molecules. We found that some miRNAs function not simply to repress protein expression levels but also expression noise. Gene expression can be variable because of chance, environmental stress, and genomic stress. Variability is especially harmful in situations where many cells in a tissue must behave uniformly, and variability is a hallmark of cancer cells. We found two conserved miRNAs that suppress the impact of all three sources of variability on gene expression. Future work will uncover the mechanisms of regulation and functionality, and explore how generally they are used in this and other species. A recent discovery by us suggests that merely reducing the protein translation capacity of cells by 50% can bypass their need for miRNAs altogether. Why this is so is another future aim. A second area of our interest seeks a biophysical understanding of tissue morphology: how do we explain the characteristic shapes and levels of organization of cellular tissues? The link between molecular forces on the subcellular (nm) scale and morphology on the tissue scale (mm) has not been made. We combine mathematical modeling and genetic experiments in Drosophila to define these links. A 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.

 描述(申请人提供)：我的研究集中在生物学的两个不同领域。我们最努力的领域涉及到小的非编码RNA的分子机制和功能。我们对两类小RNA感兴趣：microRNAs(MiRNAs)和Short Interaction RNAs(SiRNAs)。这两种蛋白都是通过对RNA前体进行DICER处理而产生的，都与ArgAerte蛋白有关，以抑制转录后基因的表达。这两类RNA对人类疾病都有巨大的影响，无论是在引起疾病方面，还是在潜在的治疗疾病方面。因此，重要的是要基本了解这些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。我们专注于在模式生物果蝇中研究这些问题，因为到目前为止在果蝇身上发现的机制和调节与人类高度相似。果蝇丰富的遗传学使功能实验成为可能，这在哺乳动物身上是不可能的。这一奖项将支持我们发现小RNA调控的新原理，并充实关于先前发现的必要的详细信息。例如，我们发现了细胞外信号来调节miRNA途径的生物发生步骤和效应步骤。游离脂肪酸信号减弱miRNA介导的抑制，而转化生长因子β信号激活miRNA前体分子的核处理。我们发现，一些miRNAs的功能不仅仅是抑制蛋白质表达水平，还可以抑制表达噪音。基因的表达可能会因偶然性、环境压力和基因组压力而变化。在组织中的许多细胞必须统一行为的情况下，可变性尤其有害，而可变性是癌细胞的标志。我们发现了两个保守的miRNAs，它们抑制了所有三个可变性来源对基因表达的影响。未来的工作将揭示调节和功能的机制，并探索它们在这个物种和其他物种中的普遍使用情况。我们最近的一项发现表明，仅仅将细胞的蛋白质翻译能力降低50%，就可以完全绕过它们对miRNAs的需求。为什么会这样，是未来的另一个目标。我们感兴趣的第二个领域寻求对组织形态的生物物理理解：我们如何解释细胞组织的特征形状和组织水平？亚细胞尺度上的分子作用力(纳米)和组织尺度上的形态(毫米)之间的联系还没有得到证实。我们结合数学建模和果蝇的遗传实验来定义这些联系。未来的方向是采用我们经过验证的方法来探索组织内细胞所经历的机械力如何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。