Neutrophil migration and inflammation

炎症表现为肿胀、发红、发热和功能丧失，并且对于恢复 损伤和感染后的组织稳态。中性粒细胞是急性炎症的主要效应细胞， 对抗感染，促进伤口愈合和炎症消退，同时有助于侧支组织 损伤此外，嗜中性粒细胞被用作穿过组织屏障将货物递送至组织的载体。 炎症部位。更好地理解嗜中性粒细胞-调节中性粒细胞的内在机制 移徙将在预防和治疗各种疾病方面具有广泛的转化重要性， 炎症相关疾病。与研究中性粒细胞相关的挑战是一组有限的遗传 工具和细胞在体内的可塑性。为了应对这些挑战，PI使用斑马鱼，一种遗传学上 具有良好保守的先天免疫系统的易处理的脊椎动物模型。中性粒细胞内在基因的研究结果 调节在斑马鱼模型中产生的中性粒细胞迁移的蛋白质然后在原代人或 鼠中性粒细胞。MicroRNA是22-24 nt的小RNA分子，其调节健康中的稳态， 疾病MicroRNA“模拟物”和“抑制剂”正在成为下一代治疗剂，因为它们具有 调节基因网络的能力。此外，microRNA被用作发现新的 生物过程的调节器。一个关键的差距仍然是了解microRNA如何调节中性粒细胞 功能：尽管在中性粒细胞和各种疾病中进行了重要的microRNA分析研究，但microRNA 功能研究很少。PI的实验室一直处于解决这一未满足需求的最前沿， 表征microRNA及其在中性粒细胞迁移中的靶点。在最近取得的进展的基础上， 该项目是继续表征microRNAs在调节中性粒细胞迁移中的作用，有两个子目标：（1.1） 鉴定作为中性粒细胞迁移和炎症的新型调节剂的microRNA靶标，和（1.2）表征 RORα如何调节中性粒细胞迁移。一个单独的项目是描述机制的特点， 线粒体在中性粒细胞迁移中的作用。线粒体分裂促进许多细胞类型的迁移， 包括淋巴细胞，可能是通过增加线粒体定位和ATP的产生，在网站的高 能源需求。相反，中性粒细胞具有高度融合的线粒体网络，主要使用 糖酵解产生ATP，这表明线粒体在ATP领域之外的其他作用。 具体而言，PI旨在（2.1）表征MFN 2如何调节中性粒细胞迁移。前提是 MFN 2介导的细胞-ER接触调节Rac活化和中性粒细胞粘附和迁移。 PI将继续（2.2）鉴定其他线粒体相关基因作为中性粒细胞的新型调节因子 迁移和炎症。增加对中性粒细胞迁移和炎症的理解将打开 细胞生物学和免疫学的多个前沿领域。此外，由于这项工作，以前探索不足， 治疗炎症性疾病的可能性将逐渐显现。

Inflammation presents as swelling, redness, heat, and lost-of-function and is essential for the restoration of tissue homeostasis after injury and infection. Neutrophils are the major effector cells of acute inflammation that combat infection, promote wound healing and resolution of inflammation, while contributing to collateral tissue injury. In addition, neutrophils are exploited as vehicles that cross tissue barriers to deliver cargos to inflammation sites. A better understanding of the neutrophil-intrinsic mechanisms that regulate neutrophil migration will have broad translational importance in the prevention and treatment of a wide range of inflammation-related diseases. The challenges associated with studying neutrophils are a limited set of genetic tools and the plasticity of the cells in vivo. To address these challenges, the PI uses zebrafish, a genetically tractable vertebrate model with a well-conserved innate immune system. Findings on neutrophil intrinsic genes that regulate neutrophil migration generated in the zebrafish model are then validated in primary human or murine neutrophils. MicroRNAs are small RNA molecules of 22-24 nt that regulate homeostasis in health and disease. MicroRNA “mimics” and “inhibitors” are emerging as next-generation therapeutics because of their ability to modulate a network of genes. In addition, microRNAs are being used as tools to discover novel regulators of biological processes. A critical gap remains understanding how microRNAs regulate neutrophil function: despite the prominent microRNA profiling studies in neutrophils and in various diseases, microRNA functional studies are scarce. The PI’s lab has been at the forefront of addressing this unmet need by characterizing microRNAs and their targets in neutrophil migration. Building on their recent progress, the first project is to continue charactering microRNAs in regulating neutrophil migration with two sub aims: (1.1) identify microRNA targets as novel regulators of neutrophil migration and inflammation, and (1.2) characterize how RORα regulates neutrophil migration. A separate project is to characterize mechanisms delineating the role of mitochondria in neutrophil migration. Mitochondria fission promotes migration in many cell types, including lymphocytes, presumably by increasing mitochondria localization and ATP production at sites of high energy demand. On contrary, neutrophils possess a highly fused mitochondrial network and primarily use glycolysis for ATP generation, suggesting additional roles of mitochondria outside the realm of ATP. Specifically, the PI seeks to (2.1) characterize how MFN2 regulates neutrophil migration. The hypothesis is that MFN2-mediated mitochondrial-ER contact regulates Rac activation and neutrophil adhesion and migration. The PI will continue to (2.2) identify additional mitochondrial related genes as novel regulators of neutrophil migration and inflammation. An increased understanding of neutrophil migration and inflammation will open multiple fronts in cell biology and immunology. Additionally, as a result of this work, previously underexplored therapeutic possibilities to treat inflammatory diseases will come to light.