Prostaglandins and actin remodeling

所有真核细胞都能产生前列腺素(PG)信号并对其作出反应。PGS是一种脂质信号分子， 具有广泛的功能，从炎症到生育再到伤口愈合。PG信令不平衡 许多疾病，如出生缺陷、心血管疾病和癌症。PGS具有如此广泛的影响是因为 PG有5种类型，每种类型都激活多个信令级联。所有PG都是通过多个步骤生产的 需要环氧合酶(COX)酶的过程。COX酶是常用的 非类固醇抗炎药(NSAID)，如阿司匹林和布洛芬。因此，非甾体抗炎药会阻止所有PG 合成和信号传递。为了开发更具体的治疗方法并更好地了解前列腺素的功能，它是 对于揭示PG信号的细胞作用是必不可少的。PGs的一个未被研究的细胞功能是调节 肌动蛋白重塑促进集体细胞迁移。虽然超过5万项研究发现了关键的 对于细胞迁移的调节，只有不到60项研究集中在PGs在这一过程中的作用。因此，如何 PGS调节肌动蛋白的重塑和迁移仍然难以捉摸。单个PG信号通路的作用， 而它们是作用于迁移细胞还是在它们的底物中协调细胞迁移，目前还知之甚少。 此外，作为PG信号下游效应器的特定肌动蛋白调节因子，以及它们是如何 在很大程度上是未知的。为了克服这些知识差距，我们利用了健壮的系统 在果蝇体内，边缘细胞在卵子发生过程中的集体迁移。在过去的五年里，我们 发现在边缘细胞中PG的合成促进了准时迁移，而在底物中PG的合成则促进了按时迁移 控制边界单元簇凝聚力。我们确定了两个边界细胞中PGs的一个下游目标 它们的底物是发束素。除了捆绑肌动蛋白外，我们还发现筋膜蛋白调节力的传递。 通过促进核骨架和细胞骨架(LINC)复合体的连接物的活性而到达细胞核， 以及通过抑制肌球蛋白在细胞之间传递力量。使用遗传、细胞、生化和 生物物理方法，拟议的研究有望建立PG信号转导的新范式，以及 它对Fasin的影响，协调迁移细胞及其细胞底物的行为，促进集体 细胞迁移。我们建议解决：1)哪个PG信号级联作用于迁移细胞，而不是它们 底物调节集体细胞迁移？2)PG信号如何调节Fasin？3)它的作用是什么？ PG信号在LINC复合体介导的迁移过程中的机械转导？4)PG信号是如何 在集体细胞迁移过程中控制迁移细胞和它们的底物之间的力量平衡？ 通过这项工作，我们希望从根本上提高我们对多重PG的机械理解 信号通路和筋膜蛋白介导力传递都在细胞内控制核动力学和 在组织内控制集体迁移。这种增长的理解可以用来开发小说 预防/治疗出生缺陷、伤口愈合并发症和癌症转移的治疗方法。

All eukaryotic cells produce and respond to prostaglandin (PG) signaling. PGs are lipid signaling molecules that have a wide range of functions from inflammation to fertility to wound healing. Imbalances in PG signaling underly many diseases, such as birth defects, cardiovascular disease, and cancer. PGs have such wide effects because there are 5 types of PGs, and each activates multiple signaling cascades. All PGs are produced by a multistep process that requires cyclooxygenase (COX) enzymes. COX enzymes are the targets of the commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. Thus, NSAIDs block all PG synthesis and signaling. To develop more specific therapies and to better understand the functions of PGs, it is essential to uncover the cellular roles of PG signaling. One understudied cellular function of PGs is to regulate actin remodeling to promote collective cell migration. While over 50,000 studies have uncovered critical regulators of cell migration, less than 60 studies have focused on the roles of PGs in this process. Thus, how PGs regulate actin remodeling and migration remains elusive. The roles of individual PG signaling pathways, and whether they act in the migratory cells or their substrate to coordinate cell migration are poorly understood. Further, the specific actin regulators that are the downstream effectors of PG signaling, and how they are modulated, are largely unknown. To overcome these knowledge gaps, we take advantage of the robust system of Drosophila and the in vivo, collective migration of the border cells during oogenesis. In the last five years, we found that PG synthesis in the border cells promotes on-time migration, whereas PG synthesis in the substrate controls border cell cluster cohesion. We identified that one downstream target of PGs in both the border cells and their substrate is Fascin. In addition to bundling actin, we found Fascin regulates the transmission of force to the nucleus by promoting the activity of the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and the transmission of force between cells by inhibiting myosin. Using genetic, cellular, biochemical, and biophysical approaches, the proposed studies are expected to build a new paradigm for how PG signaling, and its effects on Fascin, coordinate the behaviors of migrating cells and their cellular substrates to promote collective cell migration. We propose to address: 1) Which PG signaling cascades act in the migratory cells versus their substrate to regulate collective cell migration? 2) How does PG signaling regulate Fascin? 3) What is the role of PG signaling in LINC Complex-mediated mechanotransduction during migration? 4) How does PG signaling control the balance of forces between the migratory cells and their substrate during collective cell migration? Through this work, we expect to fundamentally advance our mechanistic understanding of how multiple PG signaling pathways and Fascin mediate force transmission both inside cells to control nuclear dynamics and within tissues to control collective migration. This increased understanding can be applied to develop novel therapeutics to prevent/treat birth defects, wound healing complications, and cancer metastasis.