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

描述(申请人提供)：本研究的目的是识别和确定MicroRNAs(MiRNAs)及其靶标在果蝇因病原体感染而调节先天免疫信号和肠道上皮细胞动态平衡中的作用，以提供新的见解以更好地了解它们在进化上保守的哺乳动物同行。为了应对细菌或真菌通过败血症引起的感染，免疫缺陷 或通行费信号级联分别被激活，最终导致电池的生产 强效抗菌肽(AMP)。AMP分泌到血淋巴中，起到系统防御的作用，清除入侵的病原体。此外，当通过口服等自然途径感染病原体时，果蝇肠道内会产生局部免疫反应，导致合成杀菌活性氧种和AMP。在果蝇和哺乳动物之间，天然免疫信号的分子机制非常保守。虽然入侵病原体的有效控制依赖于快速而有力的免疫信号通路的诱导，但系统或局部的长期或异常激活可能会导致人类的病理状况。因此，先天免疫信号的大小和持续时间都需要严格调控。此外，苍蝇胃肠道的病原体感染通过刺激刺激触发动态平衡反应 肠道干细胞的增殖和分化，以修复受损的组织。这种体内平衡程序的失调可能导致异常增生表型，这与人类的结直肠癌非常相似。MiRNAs是一类内源性调节的小RNA，通过序列特异性的方式抑制靶基因的表达，调节无数的生物学过程。我们推测，在果蝇对病原体感染的反应中，选择miRNAs在调节先天性免疫信号通路和肠道动态平衡方面发挥关键作用。在这里，我们建议识别和阐明这些miRNAs及其靶标在调节这些生物学过程中的作用，旨在将miRNAs整合到果蝇先天免疫信号和组织动态平衡网络中，并利用miRNAs作为工具从miRNA靶基因中发现调节这些过程的新因素。这项拟议研究的完成将建立miRNAs作为果蝇先天免疫信号和肠道内稳态的调节器，以应对病原体感染。这将促进我们对它们保守的哺乳动物同行的理解，为人类病理疾病(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。

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.