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

描述（由申请人提供）：拟议研究的目标是鉴定和确定microRNA（miRNAs）及其靶标在调节果蝇中响应病原体感染的先天免疫信号传导和肠道上皮稳态中的作用，以便提供新的见解，以更好地了解其进化保守的哺乳动物对应物。为了应对细菌或真菌感染通过脓毒性损伤，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被分泌到血淋巴中并作为系统防御剂来清除入侵的病原体。此外，在通过自然感染途径（如口服）遇到病原体时，果蝇肠道中会产生局部免疫反应，导致合成杀微生物活性氧和AMP。先天免疫信号转导的分子机制在果蝇和哺乳动物之间是非常保守的。 虽然入侵病原体的有效控制取决于免疫信号传导途径的快速和稳健诱导，但全身或局部的延长或异常激活可导致人类的病理状况。因此，先天免疫信号传导的幅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胃肠道内的蛋白质来触发稳态反应。 肠干细胞增殖和分化以修复受损组织。这种稳态程序的失调可导致异常发育表型，其与人类结直肠癌非常相似。miRNAs是一类内源性调控小RNA，通过序列特异性抑制靶基因表达来调节多种生物学过程。我们假设选择的miRNAs在调节果蝇的先天免疫信号通路和肠道内稳态应答病原体感染中起关键作用。在这里，我们建议确定和阐明这些miRNA及其靶基因在调节这些生物学过程中的作用，旨在将miRNA整合到果蝇先天免疫信号传导和组织稳态网络中，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。 该研究的完成将确立miRNAs作为先天免疫信号传导和肠道稳态的调节剂，以响应果蝇对病原体感染的反应。这将促进我们对其保守的哺乳动物对应物的理解，为人类病理条件（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剂的开发。

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.