Prostaglandins and actin remodeling

前列腺素和肌动蛋白重塑

• 批准号: 10328668
• 负责人: Tina L Tootle
• 金额: $ 55.06万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328668
• 关键词: Actins; Address; Aspirin; Behavior; Biochemical; Bundling; Cardiovascular Diseases; Cell Nucleus; Cell physiology; Cells; Complex; Congenital Abnormality; Cytoskeleton; Disease; Drosophila genus; Enzymes; Equilibrium; Eukaryotic Cell; Fertility; Genetic; Ibuprofen; Impaired wound healing; Individual; Inflammation; Knowledge; Lipids; Malignant Neoplasms; Mediating; Myosin ATPase; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Oogenesis; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Role; Signal Pathway; Signal Transduction; Signaling Molecule; System; Time; Tissues; Work; biophysical techniques; cell motility; cohesion; fascin; in vivo; insight; mechanotransduction; migration; novel therapeutics; prevent; public health relevance; transmission process; wound healing

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.

所有真核细胞都产生并响应前列腺素（PG）信号。PG是脂质信号分子， 具有从炎症到生育到伤口愈合的广泛功能。PG信号的不平衡 许多疾病，如出生缺陷，心血管疾病和癌症。PG有如此广泛的影响，因为 PG有5种类型，每种类型都会激活多个信号级联。所有的PG都是通过多步骤 需要环氧合酶（考克斯）酶的过程。考克斯酶是常用的免疫抑制剂的靶标。 非甾体抗炎药（NSAID），如阿司匹林和布洛芬。因此，NSAID阻断所有PG 合成和信号传导。为了开发更具体的治疗方法，更好地了解PG的功能， 揭示PG信号传导的细胞作用至关重要。PG的一个未充分研究的细胞功能是调节 肌动蛋白重塑，促进集体细胞迁移。超过5万项研究揭示了 作为细胞迁移的调节因子，只有不到60项研究关注PG在这一过程中的作用。因此如何 PG调节肌动蛋白重塑和迁移仍然难以捉摸。单个PG信号通路的作用， 以及它们是否在迁移细胞或其基质中起作用以协调细胞迁移，人们知之甚少。 此外，作为PG信号传导的下游效应物的特定肌动蛋白调节剂，以及它们如何与PG信号传导相关。 调制，在很大程度上是未知的。为了克服这些知识差距，我们利用强大的系统 和在体内，在卵子发生过程中的边缘细胞的集体迁移。在过去的五年里，我们 发现边缘细胞中的PG合成促进了按时迁移，而基底细胞中的PG合成 控制边界小区集群内聚性。我们在两个边缘细胞中发现了一个PGs的下游靶点， 它们的底物是Fascin。除了捆绑肌动蛋白，我们发现Fascin还调节力的传递， 通过促进核骨架和细胞骨架（LINC）复合物的接头的活性， 以及通过抑制肌球蛋白在细胞之间传递力。利用遗传、细胞、生物化学和 生物物理方法，拟议的研究预计将建立一个新的范式如何PG信号， 它对Fascin的作用，协调迁移细胞及其细胞基质的行为，促进集体迁移， 细胞迁移我们建议解决：1）哪些PG信号级联在迁移细胞中起作用， 调节集体细胞迁移的基质？2)PG信号如何调节Fascin？3)的作用是什么 PG信号在LINC复合物介导的机械转导过程中的迁移？4)PG信号是如何 在集体细胞迁移过程中，控制迁移细胞与其基质之间的力平衡？ 通过这项工作，我们期望从根本上推进我们对多个PG如何 信号通路和Fascin介导细胞内的力传递以控制核动力学， 控制集体迁移。这种增加的理解可以应用于开发新的 预防/治疗出生缺陷、伤口愈合并发症和癌症转移的治疗剂。