Collaborative Research: Ideas Lab: The Role of Extracellular RNA in Intercellular and Interkingdom Communication

合作研究：创意实验室：细胞外 RNA 在细胞间和王国间通讯中的作用

• 批准号: 2243534
• 负责人: Patricia Baldrich
• 金额: $ 102.26万
• 依托单位: Donald Danforth Plant Science Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2243534&HistoricalAwards=false
• 关键词: Collaborative; Research; Ideas; Lab; Role

This project is a collaboration among seven laboratories with diverse and complementary expertise. The overarching goal of the project is to understand the role of extracellular RNA (exRNA) in communication between cells and in shaping the community of microbes, especially bacteria, that live on and inside plants, insects, and humans. These collections of microbes are often referred to as microbiomes and are critical for the health of plants and animals, including humans. A healthy microbiome promotes a healthy immune system, but how healthy microbiomes are maintained is poorly understood. This project will test the hypothesis that RNA secreted by host cells plays a central role in maintaining health both through communication among cells and by modifying the microbiome. RNA is best known for its key role in protein production inside cells, such as in RNA-based COVID vaccines. However, not all RNA encodes proteins, and cells produce more non-coding RNA than coding RNA, some of which is actively pushed into the environment by cells. This secreted RNA appears to be taken up by other cells, including bacteria and fungi, where it could potentially impact their growth. Understanding how exRNAs shape communication between cells and organisms will enable manipulation of exRNA communication in both agriculture and medicine, which will lead to development of environmentally friendly pesticides, as well as treatments that promote formation of healthy microbiomes in both plants and animals. This knowledge will also enable development of diagnostic and therapeutic tools for early detection and/or treatment of disease.All cellular organisms secrete RNAs. The functions of these extracellular RNAs (exRNAs), however, are poorly understood. Two likely functions are intercellular and interkingdom communication. Open questions abound in exRNA biology: how are exRNAs selected for secretion, how are they targeted to recipient cells, and what are their roles in normal health and organismal fitness? Arabidopsis leaf exRNA isolates are highly enriched in the post-transcriptional modification N6-methyladenosine (m6A) (as compared to total cellular RNA) suggesting that post-transcriptional modifications may tag specific RNAs for export. Consistent with this, human exosomal microRNAs are enriched with m6A (relative to cytosolic microRNAs). Interestingly, a large number of mammalian small non-coding RNAs (ncRNAs) that localize to the external cell surface were recently found to harbor specific sialylated glycan modifications. These observations suggest that specific RNA modifications tag RNAs for cellular export and direct entry into appropriate recipient cells. This project will 1) test the hypothesis that exRNAs have specific features marking them for secretion and uptake, both within and among species, 2) determine how exRNAs are transferred from signaler to receiver cells, and 3) assess the impact of exRNA on microbiome health and composition through examining human gut, insect gut, and leaf surface models.This project was co-funded by the Directorate for Biological Sciences, and the Plant Genome Research Program and the Plant Biotic Interactions Program in the Division of Integrative Organismal Systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目是七个具有不同和互补专业知识的实验室之间的合作。该项目的首要目标是了解细胞外RNA （exRNA）在细胞间交流和塑造微生物群落中的作用，特别是细菌，它们生活在植物，昆虫和人类的体内。这些微生物群通常被称为微生物组，对包括人类在内的动植物的健康至关重要。健康的微生物群促进健康的免疫系统，但健康的微生物群是如何维持的，人们知之甚少。该项目将验证宿主细胞分泌的RNA通过细胞间的交流和修饰微生物群在维持健康方面发挥核心作用的假设。RNA最为人所知的是其在细胞内蛋白质生产中的关键作用，例如基于RNA的COVID疫苗。然而，并不是所有的RNA都编码蛋白质，细胞产生的非编码RNA比编码RNA多，其中一些是非编码RNA被细胞主动推入环境中。这种分泌的RNA似乎被其他细胞吸收，包括细菌和真菌，在那里它可能会影响它们的生长。了解exRNA如何塑造细胞和生物体之间的通讯，将有助于在农业和医学中操纵exRNA通讯，这将导致环境友好型农药的开发，以及促进植物和动物中健康微生物群形成的治疗方法。这些知识还将有助于开发早期发现和/或治疗疾病的诊断和治疗工具。所有的细胞生物都分泌rna。然而，人们对这些细胞外rna （exrna）的功能知之甚少。两种可能的功能是细胞间和王国间的通讯。在exRNA生物学中有很多悬而未决的问题：exRNA是如何被选择用于分泌的，它们是如何靶向受体细胞的，它们在正常健康和机体适应性中扮演什么角色？拟南芥叶片exRNA分离物在转录后修饰n6 -甲基腺苷（m6A）中高度富集（与总细胞RNA相比），这表明转录后修饰可能标记特异性RNA用于出口。与此一致的是，人类外泌体microRNAs富集m6A（相对于细胞质microRNAs）。有趣的是，最近发现大量定位于外细胞表面的哺乳动物小非编码rna （ncRNAs）含有特异性唾液化聚糖修饰。这些观察结果表明，特定的RNA修饰标记RNA用于细胞输出和直接进入适当的受体细胞。该项目将1)验证exRNA在物种内和物种间具有特定的分泌和摄取特征的假设，2)确定exRNA如何从信号细胞转移到接收细胞，3)通过检查人类肠道、昆虫肠道和叶片表面模型评估exRNA对微生物组健康和组成的影响。该项目由生物科学理事会、植物基因组研究计划和植物生物相互作用计划共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。