Role of microRNAs in neutrophil migration

中性粒细胞炎症推动了免疫病理，涉及许多人类疾病，包括 直接涉及免疫成分，如风湿性关节炎和那些没有明显联系的， 如糖尿病、神经退行性疾病和癌症。最近的证据表明，中性粒细胞是长的。 传播炎症的活细胞，关键地调节炎症的大小，并在 在无菌炎症和感染中的先天和获得性免疫。因此，一个成功的战略是 防止中性粒细胞的初始渗透有望显著改善炎症条件和 降低许多现代疾病的风险。中性粒细胞运动性是临床治疗的靶点 炎症性疾病，如痛风和心包炎。然而，目前的药物，如皮质类固醇和 微管失稳剂秋水仙碱缺乏中性粒细胞特异性，因此不可避免地伴随着 不良副作用。迫切需要改进现有制度，这有赖于一个更好的 了解中性粒细胞特有的调节中性粒细胞迁移的内在机制。MicroRNAs 是进化上保守的非编码小RNA，在转录后调节蛋白质合成。 最近，microRNAs和抗microRNAs已成为治疗人类疾病的策略。尽管有一份名单 在人的中性粒细胞中发现了许多microRNAs，它们在中性粒细胞迁移中的作用 有一群人还没有得到解决。缺乏这样的知识就会错失驾驭的机会。 作为预防和治疗炎症条件的工具的microRNAs。在这里，我们提出第一个 系统研究microRNAs在调节中性粒细胞迁移中的功能，旨在识别和 具有抑制中性粒细胞治疗潜力的microRNA和抗microRNA的鉴定 发炎。我们将#1.确定microRNA如何共同调节中性粒细胞的迁移。#2.筛选 抑制中性粒细胞迁移的单个microRNA。#3.确定单个miRNA如何抑制 中性粒细胞迁移。#4.开发一种分离中性粒细胞特异性miRISC的工具。我们的工作使用了斑马鱼，一种 脊椎动物模式生物，允许筛选中性粒细胞内在microRNAs在 调节中性粒细胞从造血组织到局部感染的迁移，这在 细胞培养或在小鼠体内。为了将我们的发现转化为与人类健康更相关的环境，我们将确认我们的 在人类中性粒细胞样细胞和炎症小鼠模型中的发现。我们的初步研究很强烈 建议我们已经收集了所有必要的工具并确定了候选microRNA来推动这一领域的发展 明显向前推进。我们的贡献将是巨大的，因为预计它将具有广泛的翻译 在预防和治疗各种与炎症有关的疾病方面具有重要意义。

Neutrophilic inflammation drives the immunopathology involved in numerous human diseases, including those directly involving an immune component such as rheumatic arthritis and those that are not obviously linked, such as diabetes, neurodegenerative disease and cancer. Recent evidences suggest that neutrophils are long lived cells that disseminate inflammation, critically regulate the magnitude of the inflammation and that bridge innate and adaptive immunities in both sterile inflammation and infection. Thus, a successful strategy to prevent the initial infiltration of neutrophils is expected to significantly improve inflammatory conditions and reduce the risk of many modern diseases. Neutrophil motility is targeted in clinical settings to treat inflammatory diseases such as gout and pericarditis. However, current drugs such as corticosteroids and the microtubule destabilizing agent colchicine lack neutrophil specificity thus are inevitably accompanied with adverse side effects. There is an urgent need to improve the existing regimes, which is dependent on a better understanding of the neutrophil-intrinsic mechanisms that specifically regulate neutrophil migration. MicroRNAs are evolutionarily conserved, small non-coding RNAs that post-transcriptionally regulate protein synthesis . MicroRNAs and anti-MicroRNAs have recently become strategies for treating human diseases. Although a list of microRNAs are identified in human neutrophils, their contributions in neutrophil migration as individuals or as a group have not been addressed. The absence of such knowledge creates a missed opportunity to harness microRNAs as tools in the prevention and treatment of inflammatory conditions. Here we propose the first systemic survey of the function of microRNAs in regulating neutrophil migration, aiming to identify and characterize microRNAs and anti-microRNAs with therapeutic potentials in restraining neutrophilic inflammation. We will #1. Determine how microRNAs collectively regulate neutrophil migration. #2. Screen for individual microRNAs that suppress neutrophil migration. #3. Determine how individual miRNAs suppress neutrophil migration. #4. Develop a tool to isolate neutrophil specific miRISC. Our work used zebrafish, a vertebrate model organism that allow for screenings of neutrophil intrinsic microRNAs for their contribution in regulating neutrophil migration, from the hematopoietic tissue to a localized infection, which is not possible in cell culture or in mice. To translate our findings to a more human health relevance setting, we will confirm our findings in human neutrophil like cells and inflammatory mouse models. Our preliminary studies strongly suggest that we have collected all the essential tools and identified candidate microRNAs to push this field forward significantly. Our contribution will be significant because it is expected to have broad translational importance in the prevention and treatment of a wide range of inflammation related disease.