Small RNAs as Novel Modulators of Microbe-Host Interactions

小RNA作为微生物-宿主相互作用的新型调节剂

基本信息

批准号：
10478889
负责人：
Mohamed Abou Donia
金额：
$ 150.52万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478889
关键词：
Address Affect Animal Model Animals Antibiotic Resistance Antibiotics Antisense RNA Area Bacteria Bacterial RNA Base Sequence Behavior Biological Assay Biological Markers Biology Caenorhabditis elegans Cells Chemicals Communities Computational Biology Data Development Disease Dissection Eating Elements Food Foundations Genes Genetic Transcription Genome Genomics Goals Health Healthcare High temperature of physical object Human Human Microbiome Immune Immune response Immunomodulators Infection Intervention Knowledge Lead Learning Lung Mammalian Cell Mammals Maps Mediating Mediator of activation protein Microbe Modeling Molecular Nucleic Acids Nutritional Organism Pathogenesis Patients Pharmaceutical Preparations Pharmacology Probiotics Pseudomonas aeruginosa RNA RNA Interference RNA Interference Pathway Reading Research Research Project Grants Resources Risk Role Shapes Signal Transduction Signaling Molecule Small RNA Societies Source Spielmeyer-Vogt Disease Surface Therapeutic Virulent Work antimicrobial bacteriome base combat design drug development experience flexibility gut microbiome host-microbe interactions human pathogen immune system function innovation insight microbial microbiome microbiome composition novel novel antibiotic class novel strategies novel therapeutics pathogen pathogenic bacteria resistance mechanism response small molecule success ward

项目摘要

The rise in antibiotic resistance has severely depleted our arsenal for combatting deadly bacterial pathogens. Meanwhile, despite increased appreciation of the myriad ways that microbiome bacteria impact human health, most of the signals that bacteria use to influence hosts remain unknown. This proposal seeks to address both of these challenges by leveraging our team’s unique expertise and recent discovery that animals can directly sense and respond to bacterial small RNAs (sRNAs). Since the discovery of antibiotics in the 1920s, the pathogenesis field has primarily focused on small molecules: nearly all known antibiotics and bacterial signaling molecules are small molecules. But we sorely need new, orthogonal approaches. Nucleic acid-based therapies have emerged as an exciting new platform for rapid drug development. Due to their chemical similarity, the pharmacology of nucleic acids is established, such that once we know what sequence to target, the drug development pipeline is relatively streamlined (at least in comparison to small molecule drugs). For example, a Batten disease patient was recently successfully treated with a personalized synthetic antisense RNA, less than a year after her genome was sequenced. RNA-based interventions have typically not been considered for bacteria because bacterial RNAs were thought to function exclusively within the bacteria. However, we recently overturned this paradigm by proving that model animal hosts can directly “read” the sRNAs produced by the human pathogen, Pseudomonas aeruginosa, using the RNA-interference (RNAi) machinery to respond to the bacterial sRNAs. This result is particularly exciting because it suggests a previously unappreciated role for the RNAi machinery in sensing and responding to bacteria. It also suggests that understanding sRNA-based microbe-host signaling could help develop new therapies to help hosts ward off pathogens or promote commensal colonization. However, advancing such new antimicrobial strategies is currently hindered by our lack of knowledge regarding the space of sRNA-mediated bacteria-host interactions and the molecular mechanisms by which they function. Here, we propose to build off our discovery of sRNA-host signaling to significantly close this knowledge gap. This will be accomplished in three complementary parts that span multiple hosts and microbes: globally mapping human gut microbiome community sRNA-host interactions and functions, determining how mammalian cells respond to pathogen sRNAs, and using C. elegans to characterize the molecular mechanisms of sRNA-host interactions. To achieve these goals we will combine the expertise of our team, comprised of leaders in the fields of human microbiome and computational biology (Donia), microbial pathogenesis and antibiotic development (Gitai), and C. elegans behavior and genomics (Murphy). Our combined efforts thus have the potential to establish new paradigms for microbe-host interactions and pave the way to desperately-needed new therapies.

抗生素耐药性的上升严重耗尽了我们对抗致命细菌的武器库与此同时，尽管人们越来越认识到微生物组细菌影响的多种方式。人类健康方面，细菌用来影响宿主的大部分信号仍然未知。通过利用我们团队独特的专业知识和最近发现的动物来应对这两个挑战可以直接感知细菌小RNA（sRNA）并对其做出反应。自20世纪20年代发现抗生素以来，发病机制领域主要集中在小微生物上。分子：几乎所有已知的抗生素和细菌信号分子都是小分子。需要新的、正交的方法，基于核酸的疗法已经成为一个令人兴奋的新平台。由于其化学相似性，核酸的药理学得以建立，这样，一旦我们知道了目标序列，药物开发流程就会相对简化（在至少与小分子药物相比）例如，巴顿病患者最近成功治愈。在她的基因组测序后不到一年，她接受了个性化合成反义 RNA 治疗。基于 RNA 的干预措施通常不被考虑用于细菌，因为细菌 RNA 被认为只在细菌内发挥作用然而，我们最近通过证明推翻了这一范式。模型动物宿主可以直接“读取”人类病原体假单胞菌产生的 sRNA 铜绿假单胞菌，使用 RNA 干扰 (RNAi) 机制对细菌 sRNA 做出反应，该结果是。特别令人兴奋，因为它表明 RNAi 机制在传感中发挥着以前未被认识到的作用它还表明了解基于 sRNA 的微生物-宿主信号传导可能会有所帮助。开发新疗法来帮助宿主抵御病原体或促进共生定殖。目前，由于我们缺乏相关知识，推进此类新的抗菌策略受到阻碍。 sRNA 介导的细菌-宿主相互作用的空间及其发挥作用的分子机制。在这里，我们建议在 sRNA 宿主信号传导的发现基础上进一步完善这一知识这将通过跨越多个宿主和微生物的三个互补部分来完成：全球范围内。绘制人类肠道微生物群落 sRNA-宿主相互作用和功能图谱，确定如何哺乳动物细胞对病原体 sRNA 做出反应，并使用秀丽隐杆线虫来表征分子为了实现这些目标，我们将结合我们团队的专业知识，由人类微生物组和计算生物学（Donia）、微生物领域的领导者组成发病机制和抗生素开发（Gitai），以及秀丽隐杆线虫行为和基因组学（Murphy）。因此，结合起来有可能建立微生物与宿主相互作用的新范式，并为微生物与宿主相互作用铺平道路。寻求急需的新疗法的方法。