Role of microRNAs in neutrophil migration

嗜中性炎症驱动涉及许多人类疾病的免疫病理学，包括那些 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， 例如糖尿病、神经变性疾病和癌症。最近的证据表明，中性粒细胞是长 传播炎症的活细胞，关键地调节炎症的程度， 先天性和适应性免疫在无菌炎症和感染中的作用。因此，一个成功的战略， 防止中性粒细胞的初始浸润预期将显著改善炎症状况， 降低许多现代疾病的风险。在临床环境中靶向神经元运动以治疗 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 微管去稳定剂秋水仙碱缺乏嗜中性粒细胞特异性，因此不可避免地伴随有 不良副作用迫切需要改进现有制度，这取决于更好的 了解特异性调节中性粒细胞迁移的嗜中性粒细胞内在机制。微rna 是进化上保守的小的非编码RNA，其在转录后调节蛋白质合成。 MicroRNA和抗MicroRNA最近已成为治疗人类疾病的策略。虽然一份名单 在人类中性粒细胞中鉴定了100%的microRNA，它们在中性粒细胞作为个体或作为 一个群体没有得到解决。缺乏这些知识会错过利用 microRNA作为预防和治疗炎症的工具。在这里我们提出第一个 对microRNA在调节中性粒细胞迁移中的功能进行了系统性调查，旨在鉴定和 表征在抑制嗜酸性粒细胞中具有治疗潜力的microRNA和抗microRNA 炎症我们会#1确定microRNA如何共同调节中性粒细胞迁移。#2.筛选 抑制中性粒细胞迁移的单个microRNA。#3.确定单个miRNAs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。我们的研究使用了斑马鱼， 脊椎动物模式生物，其允许筛选中性粒细胞内在microRNA，以确定它们在 调节中性粒细胞迁移，从造血组织到局部感染，这是不可能的， 细胞培养或在小鼠中。为了将我们的研究结果转化为更具人类健康相关性的环境，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 这表明我们已经收集了所有必要的工具，并确定了候选microRNA，以推动这一领域的发展 向前显着。我们的贡献将是重大的，因为它预计将有广泛的翻译 在预防和治疗广泛的炎症相关疾病中的重要性。

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.