GPCR signaling during embryonic organ formation

胚胎器官形成过程中的 GPCR 信号传导

• 批准号: 10584164
• 负责人: Deborah J Andrew
• 金额: $ 42.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584164
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Actins; Adult; Affect; Animals; Apical; Autonomic nervous system; Cell Polarity; Cell Shape; Cell Survival; Cell membrane; Cell surface; Cells; Central Nervous System; Collaborations; Complement; Conflict (Psychology); Cues; Destinations; Development; Developmental Process; Dictyostelium; Disease; Distant; Drosophila garnet protein; Drosophila genome; Drosophila genus; Drug Targeting; Embryo; Embryonic Development; Enzymes; Epithelium; Erinaceidae; Event; Extracellular Matrix; Extravasation; F-Actin; FDA approved; Fogs; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Genetic; Germ Cells; Glutaminase; Hormones; Human; Immune; Immunity; Inflammation; Injury; Life; Ligands; Light; Link; Mediating; Membrane; Molecular; Molecular Mechanisms of Action; Morphogenesis; Neoplasm Metastasis; Neurotransmitters; Odors; Organ; Organism; Organogenesis; Oxidoreductase; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Pheromone; Photons; Play; Polymers; Positioning Attribute; Process; Proteins; RNA Interference; Receptor Activation; Reporting; Role; Salivary Glands; Signal Pathway; Signal Transduction; Site; Smell Perception; Smog; Somatic Cell; Source; Stimulus; Structure of primordial sex cell; System; Taste Perception; Testing; Time; Tissues; Tube; Visual; Wing; Work; cell motility; constriction; cost; genome wide screen; in vivo; insight; lipid phosphate phosphatase; migration; neuroblast; novel; polymerization; pressure; receptor; receptor binding; receptor function; recruit; response; smoothened signaling pathway; tissue/cell culture; tool

G-protein coupled receptors (GPCRs) are critical for almost every aspect of animal life. These proteins are embedded in the cell membrane and allow us to sense and respond to light, smells, and taste. GPCRs also control responses in both our central and autonomic nervous systems, and they regulate both inflammation and immunity. GPCRs control cell migration for normal development and during cancer metastasis. Indeed, approximately 34% of FDA-approved drugs target GPCRs. Nonetheless, despite decades of study, many GPCRs have no known function, their ligands remain unidentified, and the pathways through which they elicit distinct cellular responses remain mostly uncharacterized. Here, we propose to take the first steps toward understanding the roles of GPCRs during development in the experimental system of the Drosophila embryo, which has numerous advantages in terms of visual accessibility, an extensive armamentarium of genetic tools, and relatively low cost. We begin with an analysis of the Drosophila GPCR Tre1, which has been implicated in germ cell (GC) navigation and survival, extravasation of immune cell to sites of injury, and polarization of neuroblasts. We have recently reported that non-canonical Hedgehog signaling works through the Tre1 receptor to control GC navigation, resolving a long-standing conflict regarding the role of Hh in this process and revealing a novel pathway downstream of Tre1 activation. In the first aim, we uncover the molecular and cellular mechanisms through which each step of this pathway is mediated – from receptor binding to actin polymerization. We ask if and how other genes that affect GC migration work through this pathway to repel GCs (in the case of the Wunen lipid phosphate phosphatases) or attract GCs (in the case of HMGCoA reductase). Tre1 is also expressed in the forming salivary gland (SG), a tissue that, unlike GCs, migrates as a fully polarized epithelial collective. We ask if Hh signaling and Tre1 also function in the SG for its navigation and we ask if Tre1 function in this tissue complements or antagonizes the function of another GPCR – Mthl5 – which is expressed in the SG at about the same time and that has also been implicated in Hh signaling. Finally, we establish a pipeline to screen all of the GPCRs encoded in the Drosophila genome and expressed in embryos for roles in the development of either GCs or the SG. Our pilot screen has already identified two GPCRs with phenotypes consistent with important functions, one gene with a potential role in GC survival and the other with a potential role in regulating the SG extracellular matrix.

G蛋白偶联受体(GPCRs)在动物生活的几乎方方面面都是至关重要的。这些 蛋白质嵌入细胞膜，使我们能够感知和响应光、气味、 和品味。GPCRs还控制我们的中枢和自主神经系统的反应， 而且它们同时调节炎症和免疫力。GPCRs控制细胞正常迁移 在癌症的发展和转移过程中。事实上，大约34%的FDA批准的药物 目标是GPCRs。然而，尽管经过了几十年的研究，许多GPCRs并不具有已知的功能， 它们的配体以及它们引发不同细胞的途径仍未确定 人们的反应大多还没有定论。在这里，我们建议采取第一步，以 理解GPCRs在实验系统发展中的作用 果蝇胚胎在视觉可及性方面有许多优势， 基因工具种类繁多，成本相对较低。 我们从分析果蝇GPCRTre1开始，它与细菌有关 细胞(GC)导航和存活，免疫细胞外溢到损伤部位，以及极化 神经母细胞的数量。我们最近报道了非规范刺猬信号的工作原理 通过Tre1受体控制GC导航，解决了长期存在的 HH在这一过程中的作用并揭示了Tre1激活下游的一条新途径。在……里面 第一个目标，我们揭示分子和细胞机制，通过它每一步 途径是中介的--从受体结合到肌动蛋白聚合。我们问其他人是否以及如何 影响GC迁移的基因通过这一途径作用于排斥GC(在 Wunen脂肪磷酸酶)或吸引GC(在HMGCoA还原酶的情况下)。Tre1 也在形成唾液腺(SG)中表达，与GC不同的是，SG组织作为一种 完全极化的上皮性集体。我们询问HH信令和Tre1是否也在SG中为ITS发挥作用 我们问，Tre1在这个组织中的功能是补充还是对抗 另一个GPCR-Mthl5-大约在同一时间在SG中表达，它也 与HH信号有关。最后，我们建立了一个管道来筛选所有的GPCR 在果蝇基因组中编码并在胚胎中表达，在果蝇的发育中发挥作用 要么是GCS，要么是SG。我们的试点筛查已经确定了两个具有表型的GPCR 与重要功能一致，一个基因对GC生存有潜在作用，另一个基因 具有潜在的调节SG细胞外基质的作用。