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Receptor-mediated signaling pathways leading to phosphatidic acid generation

导致磷脂酸生成的受体介导的信号通路

基本信息

批准号：
9218361
负责人：
ALAN R. BRASH
金额：
$ 28.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-13 至 2018-01-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9218361
关键词：
1-Phosphatidylinositol 3-Kinase Acetyl Coenzyme A Anabolism Astrocytoma Bacteria Bacterial Genes Binding Bioenergetics Cell Line Cell Surface Receptors Cells Cellular Structures Communicable Diseases Communication Complex Development Diacylglycerol Kinase Diglycerides Disease Environment FRAP1 gene Feedback Fostering G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Generations Glioblastoma Glycerophospholipids Guanosine Triphosphate Phosphohydrolases Human Pathology Immune Isoenzymes Laboratories Lipids Malignant Neoplasms Mammalian Cell Maps Mediating Membrane Lipids Metabolic Metabolic Pathway Metabolism Modification Molecular Muscarinic M1 Receptor Neurodegenerative Disorders Nutrient Oncogenic Organism Pathway interactions Phosphatidic Acid Phospholipase C Phospholipase D Phospholipases A Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Positioning Attribute Post-Translational Protein Processing Process Production Protein Kinase Protein Kinase C RNA Interference Receptor Activation Receptor Signaling Reporting Role Second Messenger Systems Signal Pathway Signal Transduction Signal Transduction Pathway Stimulus Stress The Sun Viral Virulence Factors Virus Diseases alpha-glycerophosphoric acid cell motility cellular targeting design extracellular member metabolomics new therapeutic target novel phospholipase inhibitor phosphoproteomics receptor receptor-mediated signaling response rho GTP-Binding Proteins sensor

项目摘要

PROJECT SUMMARY A plethora of receptor-mediated signaling pathways initiate production of the lipid messenger phosphatidic acid (PtdOH). Direct activation of phospholipase D (PLD) leads to distinctive molecular species of PtdOH that bind to a variety of cellular targets. A less direct pathway is the receptor-mediated process of phospholipase C (PLC) generation of diacylglycerol with subsequent lipid phosphorylation via diacylglycerol kinase (DGK) leading to downstream production of PtdOH. A third pathway includes direct de novo generation of PtdOH via the Kennedy Pathway. Surprisingly, these pathways from cell surface receptors and constitutively activated pathways leading to PtdOH production are largely uncharacterized. While some of the signaling components such as Arf GTPases, Rho GTPases, protein kinase C, among others have been identified, a well detailed map elucidating the network has not as yet been charted. In this project we use a multi-omics approach to identify key components of these phosphatidic acid signaling pathways looking at the downstream effectors, consequences to membrane lipid composition, intracellular metabolic pathways, innate immune components and other targets of phosphatidic acid signaling. This will provide a basis for understanding how phosphatidic acid signaling contributes to a number of important human pathologies that includes cancer, infectious diseases, and neurodegenerative disorders.

项目摘要过多的受体介导的信号通路启动脂质信使磷脂酸的产生（PtdOH）。磷脂酶D（PLD）的直接活化导致独特的PtdOH分子种类，针对多种细胞目标。一个不太直接的途径是磷脂酶C的受体介导的过程 (PLC)通过二酰基甘油激酶（DGK）产生二酰基甘油，随后进行脂质磷酸化导致PtdOH的下游生产。第三种途径包括通过直接从头产生PtdOH。肯尼迪大道令人惊讶的是，这些途径从细胞表面受体和组成性激活导致PtdOH产生的途径在很大程度上是未表征的。虽然一些信号成分如Arf GTP酶、Rho GTP酶、蛋白激酶C等，已经鉴定出了非常详细的图谱，目前尚未绘制出详细的网络图。在这个项目中，我们使用多组学方法来识别这些磷脂酸信号传导途径的关键组分着眼于下游效应物，对膜脂质组成、细胞内代谢途径、先天免疫成分的影响以及磷脂酸信号传导的其他靶点。这将为理解磷脂酸信号传导导致许多重要的人类病理学，包括癌症、感染性疾病、癌症、癌症和癌症。疾病和神经退行性疾病。