Regulation of lipin phosphatidic acid phosphatase activity

在此输入文本，它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/鉴定磷脂酸性磷酸酶(PAP)活性以来，已有50多年的历史。这种酶活性统一了现在所知的磷脂酰胆碱合成的肯尼迪途径。编码PAP的基因被称为Lipin1-3，位于甘油脂合成的Kennedy途径的一个重要分支点。与三酰甘油合成途径中的其余酶不同，脂类是胞浆蛋白，从胞浆转移到它们在内膜上的作用部位。脂蛋白家族成员功能等位基因的缺失在小鼠和人类中都会导致严重的代谢和炎症障碍，而脂蛋白基因的多态与许多代谢状况有关。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，但它们到底是如何被调控的，仍然没有明确的定义。阐明控制脂质家族活性的机制和途径将有助于深入了解甘油脂的生物合成及其被干扰时的病理生理后果，并将为这些疾病的药物干预开辟新的途径。这项提案对Lipin 1的调节进行了严格和全面的研究，目的是了解其PAP活性是如何受到生化控制的。我们将表征两种激酶对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，我们还将确定脂类PAP活性的失调如何影响细胞功能，特别是中性和磷脂的合成。鉴于脂类的遗传改变所表现出的显著表型，实现这些目标将对脂类生物合成途径以及临床相关病理产生重要的见解。

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.