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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.

项目总结过多的受体介导的信号通路启动了脂质信使磷脂酸的产生 (PtdOH)。磷脂酶D(PLD)的直接激活导致结合PtdOH的独特分子物种不同的细胞目标。一种不太直接的途径是受体介导的磷脂酶C过程 (PLC)通过二酰甘油激酶(DGK)随后的脂质磷酸化生成二酰基甘油导致PtdOH的下游生产。第三条途径包括PtdOH的直接从头生成肯尼迪大道。令人惊讶的是，这些途径来自细胞表面受体并被结构性激活导致PtdOH产生的途径在很大程度上是未知的。而一些信令组件如Arf GTP酶、Rho GTP酶、蛋白激酶C等都已被确定，这是一个非常详细的图谱对该网络的澄清尚未绘制成图表。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通路的关键组件查看下游效应器，对膜脂组成、细胞内代谢途径、先天免疫成分的影响和其他磷脂酸信号的靶标。这将为理解磷脂是如何酸性信号与许多重要的人类病理有关，包括癌症、传染性疾病疾病和神经退行性疾病。