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

• 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
• 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

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.

抗生素耐药性的升高已严重耗尽了我们的武器库，以对抗致命细菌 病原体。同时，任务增加了对微生物细菌影响的多种方式的欣赏 人类健康，细菌用来影响宿主的大多数信号仍然未知。该提议试图 通过利用我们团队的独特专业知识和最近发现动物的发现，以应对这两个挑战 可以直接感知并响应细菌小RNA（SRNA）。 自1920年代发现抗生素以来，发病机场主要集中在小 分子：几乎所有已知的抗生素和细菌信号分子都是小分子。但是我们非常努力 需要新的正交方法。基于核酸的疗法已成为一个令人兴奋的新平台 快速的药物开发。由于它们的化学相似性，建立了核酸的药理学， 这样一旦我们知道针对目标的顺序，药物开发管道就会相对精简（在 与小分子药物相比至少）。例如，最近成功地成功地 用个性化的合成反义RNA处理，在测序其基因组不到一年后。 基于RNA的干预措施通常不考虑细菌，因为细菌RNA为 被认为仅在细菌中起作用。但是，我们最近通过证明 该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 铜绿菌，使用RNA干扰（RNAi）机械对细菌的反应。这个结果是 特别令人兴奋，因为它暗示了传感器中RNAi机械的先前未引起的作用 并回应细菌。它还表明，了解基于SRNA的微生物宿主信号传导可以帮助 开发新的疗法，以帮助托管病原体或促进共生殖民化。然而， 目前，我们缺乏关于 SRNA介导的细菌宿主相互作用的空间及其功能的分子机制。 在这里，我们建议建立对SRNA-HOST信号的发现，以显着关闭这些知识 差距。这将在跨越多个宿主和微生物的三个完整部分中完成：全球 映射人类肠道微生物组社区SRNA-HOST的相互作用和功能，确定如何 哺乳动物细胞对病原体SRNA反应，并使用秀丽隐杆线虫来表征分子 SRNA-HOST相互作用的机制。为了实现这些目标，我们将结合团队的专业知识， 在人类微生物组和计算生物学（DONIA），微生物领域的领导者完成 发病机理和抗生素发育（Gitai）以及秀丽隐杆线虫的行为与基因组学（Murphy）。我们的 因此，合并的努力有潜力为微生物 - 宿主相互作用建立新的范例，并铺平 迫切需要新疗法的方法。