Mechanisms and functions of cell surface glycoRNAs
细胞表面糖RNA的机制和功能
基本信息
- 批准号:10712185
- 负责人:
- 金额:$ 44.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-14 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AnabolismBiochemicalBiogenesisBiological AssayBiologyBiophysicsCaenorhabditis elegansCarbohydratesCarboxylic AcidsCell CommunicationCell modelCell physiologyCell surfaceCellsCellular biologyChemicalsCommunitiesComplexDiagnosticDissectionEngineeringEnvironmentEukaryotaExclusionFission YeastGeneticGlycobiologyHybridsImageIntracellular SpaceLabelLinkMammalian CellMetabolicMethodsModalityMolecularNatureNeighborhoodsOrganismPathogenicityPathway interactionsPlayPolymersPolysaccharidesPositioning AttributeProkaryotic CellsRNAReceptor SignalingRegulationReporterRoleSaccharomyces cerevisiaeSignal TransductionSurfaceTherapeuticTherapeutic InterventionWorkYeastscell typefield studyglycosylationimmunoregulationinnovationnovelnovel strategiespathogenreceptorsialic acid binding Ig-like lectintooltool development
项目摘要
PROJECT SUMMARY/ ABSTRACT
The cell surface is a platform for physical and regulatory control over cell biology, positioning it to be a key
interface for diagnostic targeting and therapeutic intervention. While RNA is a central polymer in biology most
thought and experimental effort devoted to RNA biology has been confined to intracellular spaces and excluded
from participating in cell surface biology. On the cell surface, carbohydrate polymers (glycans) are of critical
importance due to biophysical and signaling activities. Interestingly, despite both polymers playing central roles
in biology, RNA and glycans have largely existed in entirely non-overlapping fields of study. However, my work
has provided evidence of a hybrid molecule, an RNA-glycan conjugate (glycoRNA); this new class of biomolecule
represents a direct link between RNA and glycobiology. Critically, glycoRNAs are localized to the external
surface of living cells and can engage with immunomodulatory Siglec receptors. Thus, glycoRNAs are positioned
on a surface of critical regulatory importance, with access to cell-cell interactions, pathogens, and signaling
receptors on the cell surface. However, we currently lack facile tools to study this new cell surface molecule, we
do not understand the molecular or atomic composition of glycoRNAs, and we have a poor understanding of
how many species biosynthesize glycoRNAs. This MIRA proposal is focused on developing and implementing
methods to uncover functional roles of RNA glycosylation and we will approach the complex biology of
glycoRNAs in a systematic fashion. Initially we will develop novel chemical approaches to label glycans in the
context of RNA. My proposed strategy of selective carboxylic acid labeling represents an innovative new
approach to detecting glycoRNA, without the need for synthetic metabolic reporters. These tools will be easily
implemented across cell types and species enabling others in the scientific community. We will apply these tools
and other molecular assays to expand our understanding of the composition of the cell surface in the context of
glycoRNA. Biochemical, biophysical, and imaging-based strategies will be used to define the molecular
neighborhoods of glycoRNAs as well as the chemical nature of the RNA-glycan linkage; all together providing a
more complete picture of the mammalian cell surface. Finally, we will develop the first evidence of glycoRNAs in
non-mammalian organisms. First focusing on two major strains of yeast (S. cerevisiae and S. pombe) with robust
culturing, functional, and genetic tools that will allow for rapid dissection of the biogenesis pathway for eventual
engineering purposes. Expanding to other organisms including prokaryotes (pathogenic and not) as well as other
multicellular eukaryotes like C. elegans will better define the scope of glycoRNA biosynthesis and more robustly
equip us to generate synthetic glycoRNAs. More broadly, we intend to advance the general model of how cells
interact with each other, pathogens, and exogenous molecules, as without cell surface glycoRNAs, they are
likely incomplete. This proposal develops innovative methods to establish new conceptual and physical layers
of regulation between a cell and its environment.
项目摘要/摘要
细胞表面是对细胞生物学进行物理和调节控制的平台,
用于诊断靶向和治疗干预的接口。虽然RNA是生物学中最重要的聚合物,
致力于RNA生物学的思想和实验努力一直局限于细胞内空间,
参与细胞表面生物学。在细胞表面,碳水化合物聚合物(聚糖)是关键的
由于生物物理和信号活动的重要性。有趣的是,尽管这两种聚合物都发挥着核心作用,
在生物学中,RNA和聚糖在很大程度上存在于完全不重叠的研究领域。然而,我的工作
已经提供了一种杂交分子的证据,一种RNA-聚糖缀合物(glycoRNA);这类新的生物分子
代表了RNA和糖生物学之间的直接联系。关键的是,糖RNA定位于细胞外部,
在活细胞的表面上,可以与免疫调节性Siglec受体结合。因此,糖RNA定位于
在具有关键调控重要性的表面上,可以接触细胞间相互作用、病原体和信号传导
细胞表面的受体。然而,我们目前缺乏研究这种新细胞表面分子的简单工具,
不了解糖RNA的分子或原子组成,我们对糖RNA的理解也很差。
有多少种生物合成糖RNA。该MIRA提案的重点是制定和实施
方法来揭示RNA糖基化的功能作用,我们将探讨复杂的生物学,
glycoRNA在系统的方式。最初,我们将开发新的化学方法来标记聚糖在
RNA的背景我提出的选择性羧酸标记策略代表了一种创新的新方法,
检测糖RNA的方法,而不需要合成的代谢报告。这些工具将很容易
跨细胞类型和物种实施,使科学界的其他人能够。我们将使用这些工具
和其他分子测定,以扩大我们对细胞表面组成的理解,
糖RNA生物化学、生物物理学和基于成像的策略将被用于确定分子水平。
糖RNA的邻域以及RNA-聚糖键的化学性质;所有这些共同提供了一个
更完整的哺乳动物细胞表面图像。最后,我们将开发糖RNA的首次证据,
非哺乳类生物。首先集中在两个主要的酵母菌株(S。酿酒酵母和S. pombe)与鲁棒
培养,功能和遗传工具,将允许快速解剖生物发生途径,
工程目的。扩展到其他生物体,包括原核生物(致病性和非致病性)以及其他
多细胞真核生物如C.线虫将更好地定义糖RNA生物合成的范围,
使我们能够合成糖RNA。更广泛地说,我们打算推进细胞如何
由于没有细胞表面糖RNA,它们与彼此、病原体和外源分子相互作用,
可能不完整。该提案开发了建立新的概念和物理层的创新方法
细胞和环境之间的调节。
项目成果
期刊论文数量(0)
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