The Role of microRNAs in Modulating Innate Immunity Signaling and Gut Homeostasis

microRNA 在调节先天免疫信号和肠道稳态​​中的作用

• 批准号: 8826019
• 负责人: Rui Zhou
• 金额: $ 24.38万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826019
• 关键词: Autoimmunity; Bacterial Infections; Biochemical; Biological Process; Cell Differentiation process; Cell Proliferation; Colorectal Cancer; Development; Disease; Drosophila genus; Dysplasia; Epithelial; Family; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genomics; Goals; Health; Hemolymph; Homeostasis; Human; Immune; Immune response; Immunity; Infection; Inflammatory; Inflammatory Bowel Diseases; Ingestion; Injury; Intestines; Invaded; Lead; Malignant Neoplasms; Mammals; Mediating; Messenger RNA; MicroRNAs; Molecular; Mycoses; Natural Immunity; Nucleotides; Oral; Phenotype; Play; Porifera; Process; Production; Reactive Oxygen Species; Regulation; Role; Route; Signal Pathway; Signal Transduction; Small RNA; Stem cells; Therapeutic Agents; Tissues; Toll-like receptors; adaptive immunity; antimicrobial peptide; combat; cytokine; fitness; fly; in vivo; insight; microbial; microbicide; novel; pathogen; programs; repaired; response; self-renewal; septic; tissue regeneration; tissue repair; tool; transcription factor

DESCRIPTION (provided by applicant): The goal of the proposed study is to identify and determine the role of microRNAs (miRNAs) and their targets in modulating innate immunity signaling and gut epithelial homeostasis in response to pathogen infection in Drosophila, in order to provide new insights to better understand their evolutionarily conserved mammalian counterparts. In response to bacterial or fungal infection via septic injury, the immune deficiency or Toll signaling cascades, respectively, are activated, culminating in the production of a battery of potent antimicrobial peptides (AMPs). AMPs are secreted into the hemolymph and function as systemic defense agents to clear invading pathogens. In addition, upon encountering pathogens via natural routes of infection such as oral ingestion, a local immune response is mounted in the Drosophila gut, leading to the synthesis of microbicidal reactive oxygen species and AMPs. The molecular mechanism underlying innate immunity signaling is remarkably conserved between flies and mammals. While effective control of invading pathogens depends on rapid and robust induction of immunity signaling pathways, prolonged or aberrant activation, either systemically or locally, can lead to pathological conditions in humans. Therefore, both the magnitude and duration of innate immunity signaling need to be tightly regulated. In addition, pathogen infection of the fly gastrointestinal tract triggers a homeostatic response by stimulating intestinal stem cell proliferation and differentiation to repair damaged tissues. Dysregulation of this homeostatic program can cause a dysplasia phenotype that remarkably resembles colorectal cancer in humans. miRNAs are a class of endogenous regulatory small RNAs that modulate myriad biological processes by repressing target gene expression in a sequence-specific manner. We hypothesize that select miRNAs play a key role in regulating innate immunity signaling pathways and gut homeostasis in response to pathogen infection in Drosophila. Here we propose to identify and elucidate the role of these miRNAs and their targets in modulating these biological processes, aiming to both integrate miRNAs into the Drosophila innate immunity signaling and tissue homeostasis network and to exploit miRNAs as tools to uncover from miRNA target genes novel factors that regulate these processes. Completion of the proposed study will establish miRNAs as modulators of innate immunity signaling and gut homeostasis in response to pathogen infection in Drosophila. This will advance our understanding of their conserved mammalian counterparts, provide new insights to the mechanisms underlying human pathological conditions such as autoimmunity, inflammatory diseases and cancer, and may facilitate the development of therapeutic agents to treat these devastating disorders.

描述（由申请人提供）：拟议研究的目标是识别和确定 microRNA (miRNA) 及其靶标在调节果蝇病原体感染的先天免疫信号和肠道上皮稳态中的作用，以便提供新的见解，以更好地了解其在进化上保守的哺乳动物对应物。为了应对通过化脓性损伤引起的细菌或真菌感染，免疫缺陷 或 Toll 信号级联分别被激活，最终产生电池 有效的抗菌肽（AMP）。 AMP 分泌到血淋巴中，作为全身防御剂清除入侵的病原体。此外，当通过自然感染途径（例如口服摄入）遇到病原体时，果蝇肠道会产生局部免疫反应，导致杀菌活性氧和 AMP 的合成。先天免疫信号传导的分子机制在果蝇和哺乳动物之间非常保守。 虽然对入侵病原体的有效控制取决于免疫信号通路的快速和强有力的诱导，但长期或异常的激活，无论是全身性的还是局部性的，都可能导致人类的病理状况。因此，先天免疫信号的强度和持续时间都需要严格调节。此外，苍蝇胃肠道的病原体感染通过刺激来触发稳态反应 肠道干细胞增殖和分化以修复受损组织。这种稳态程序的失调会导致异常增殖表型，与人类结直肠癌非常相似。 miRNA 是一类内源性调节性小 RNA，通过以序列特异性方式抑制靶基因表达来调节多种生物过程。我们假设，果蝇中特定的 miRNA 在调节先天免疫信号通路和肠道稳态​​以应对病原体感染方面发挥着关键作用。在这里，我们建议识别和阐明这些 miRNA 及其靶标在调节这些生物过程中的作用，旨在将 miRNA 整合到果蝇先天免疫信号和组织稳态网络中，并利用 miRNA 作为工具，从 miRNA 靶基因中发现调节这些过程的新因子。 拟议研究的完成将确定 miRNA 作为先天免疫信号和肠道稳态​​的调节剂，以应对果蝇病原体感染。这将增进我们对它们保守的哺乳动物对应物的理解，为人类病理状况（例如自身免疫、炎症性疾病和癌症）的潜在机制提供新的见解，并可能促进治疗这些破坏性疾病的治疗药物的开发。