Neutrophil migration and inflammation

炎症表现为肿胀、发红、发热和丧失功能，是恢复 损伤和感染后的组织动态平衡。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，同时促进侧支组织 受伤。此外，中性粒细胞被用作跨越组织屏障的载体，将货物运送到 炎症部位。更好地理解中性粒细胞调节中性粒细胞的内在机制 移徙在预防和治疗各种疾病方面具有广泛的转化重要性。 与炎症相关的疾病。与研究中性粒细胞相关的挑战是一组有限的基因 工具和体内细胞的可塑性。为了应对这些挑战，PI使用了斑马鱼，一种遗传的 易驯服的脊椎动物模型，具有完好的天然免疫系统。中性粒细胞内源性基因的研究进展 在斑马鱼模型中产生的调节中性粒细胞迁移的分子随后在原始人或 小鼠中性粒细胞。MicroRNAs是22-24个核苷酸的小RNA分子，调节健康和 疾病。MicroRNA“模拟”和“抑制剂”正在成为下一代治疗药物，因为它们 调节基因网络的能力。此外，microRNAs还被用作发现新奇事物的工具 生物过程的调节者。一个关键的差距仍然是理解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有突出的microRNA图谱研究，但microRNA 功能研究很少。PI的实验室一直处于解决这一未得到满足的需求的前沿，通过 中性粒细胞迁移过程中的microRNA及其靶标的特征。在他们最近进展的基础上，第一 该项目将继续确定microRNA在调节中性粒细胞迁移方面的特征，有两个子目标：(1.1) 确定microRNA靶标作为中性粒细胞迁移和炎症的新调节因子，并(1.2)表征 RoRα如何调控中性粒细胞迁移。另一个单独的项目是描述描述 线粒体在中性粒细胞迁移中的作用。线粒体的分裂促进了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高密度脂蛋白部位的三磷酸腺苷的产生 能源需求。相反，中性粒细胞拥有高度融合的线粒体网络，主要用于 糖酵解对三磷酸腺苷的生成，提示线粒体在三磷酸腺苷领域之外的其他作用。 具体地说，PI试图(2.1)描述Mfn2是如何调节中性粒细胞迁移的。假设是这样的 Mfn2介导的线粒体-内质网接触调节RAC的激活和中性粒细胞的黏附和迁移。 PI将继续(2.2)确定更多的线粒体相关基因作为中性粒细胞的新调节因子 迁移和炎症。对中性粒细胞迁移和炎症的更多了解将开启 细胞生物学和免疫学的多个前沿领域。此外，作为这项工作的结果，以前未被探索的 治疗炎症性疾病的治疗可能性将会浮出水面。

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.