Regulation of lipin phosphatidic acid phosphatase activity

脂质磷脂酸磷酸酶活性的调节

• 批准号: 10540703
• 负责人: Thurl E. Harris
• 金额: $ 34.92万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540703
• 关键词: Affect; Alleles; Amino Acids; Anabolism; Biochemical; Cell Line; Cell Nucleus; Cell physiology; Cullin Proteins; Cytosol; Data; Diglycerides; Disease; Enzymatic Biochemistry; Enzymes; Event; F Box Domain; FRAP1 gene; Family; Family member; Gene Expression; Genes; Genetic; Genetic Polymorphism; Goals; Health; Human; In Vitro; Inflammatory; Intervention; Laboratories; Lecithin; Link; Lipids; Location; Mediating; Membrane; Metabolic; Metabolic Control; Metabolism; Mus; Mutation; Null Lymphocytes; Pathology; Pathway interactions; Phenotype; Phosphatidate Phosphatase; Phosphatidic Acid; Phospholipids; Phosphorylation; Phosphotransferases; Physiological; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Production; Protein Dephosphorylation; Protein Isoforms; Protein translocation; Publishing; Recommendation; Regulation; Role; Serine; Signal Transduction; Site; Specificity; System; Testing; Text; Transcription Coactivator; Triglycerides; Ubiquitination; Vertebrates; Yeasts; blood glucose regulation; clinically relevant; experimental study; glycogen synthase kinase 3 beta; improved; insight; lipid biosynthesis; lipine; loss of function; member; mutant; novel; pharmacologic; stoichiometry; trafficking

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. It has been more than 50 years since Eugene Kennedy described/identified phosphatidic acid phosphatase (PAP) activity. This enzymatic activity unified what is now known as the Kennedy pathway of phosphatidylcholine synthesis. The genes encoding PAP, termed Lipin 1-3, sit at an important branch point in the Kennedy pathway of glycerolipid synthesis. Unlike the remainder of the enzymes in the triacylglycerol synthesis pathway, the lipins are cytosolic proteins that translocate from the cytosol to their site of action at internal membranes. Loss of function alleles of lipin family members results in profound metabolic and inflammatory disturbances in both mice and humans, and lipin polymorphisms are linked to a number of metabolic conditions. But while genetics has demonstrated the importance of these enzymes in health and disease, precisely how they are regulated is still poorly defined. Elucidating the mechanisms and pathways controlling lipin family activity will provide insight into glycerolipid biosynthesis and the pathophysiological consequences when it is disrupted, and will open new avenues for pharmacological interventions for these diseases. This proposal undertakes a rigorous and comprehensive examination of lipin 1 regulation with the goal of understanding how its PAP activity is biochemically controlled. We will characterize the effects of two kinases on lipin 1 PAP activity and stability and identify how these regulatory events occur. In addition, we will determine how dysregulation of lipin PAP activity impacts cellular function, particularly neutral and phospholipid synthesis. Given the striking phenotypes displayed by genetic alterations in the lipins, accomplishing these aims will yield important insights into lipid biosynthetic pathways as well as clinically relevant pathologies.

在此处输入文本，这是您的应用程序的新摘要信息。此部分不得超过30行文本。 自尤金肯尼迪描述/鉴定磷脂酸磷酸酶（PAP）活性以来，已有50多年的历史。这种酶活性统一了现在被称为磷脂酰胆碱合成的肯尼迪途径。编码PAP的基因，称为Lipin 1-3，位于甘油脂合成的Kennedy途径中的重要分支点。与三酰甘油合成途径中的其余酶不同，脂蛋白是从细胞溶质易位到其在内膜的作用位点的细胞溶质蛋白。脂蛋白家族成员的功能等位基因的丧失导致小鼠和人类的严重代谢和炎症紊乱，并且脂蛋白多态性与许多代谢病症相关。但是，尽管遗传学已经证明了这些酶在健康和疾病中的重要性，但它们的确切调节方式仍然没有得到很好的定义。阐明控制脂蛋白家族活性的机制和途径将提供对甘油脂质生物合成及其被破坏时的病理生理后果的深入了解，并将为这些疾病的药物干预开辟新的途径。该提案对lipin 1的调节进行了严格而全面的检查，目的是了解其PAP活性如何受到生化控制。我们将描述两种激酶对lipin 1 PAP活性和稳定性的影响，并确定这些调节事件是如何发生的。此外，我们将确定脂蛋白PAP活性失调如何影响细胞功能，特别是中性和磷脂合成。鉴于脂蛋白的遗传改变所显示的惊人表型，实现这些目标将产生对脂质生物合成途径以及临床相关病理学的重要见解。