Regulation of Cell Phospholipid Metabolism by Phospholipase A2

磷脂酶 A2 对细胞磷脂代谢的调节

• 批准号: 0212213
• 负责人: Suzanne Barbour
• 金额: $ 38.5万
• 依托单位: Virginia Commonwealth University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0212213&HistoricalAwards=false
• 关键词: Regulation; Cell; Phospholipid; Metabolism; Phospholipase

The regulation of glycerophospholipid metabolism is fundamental to cell homeostasis as these molecules have important roles in both membrane structure and cell signaling. Recent studies indicate that the 80 kDa calcium-independent phospholipase A2 (iPLA2) plays a fundamental role in the regulation of phospholipid metabolism. This study is intended to further elucidate the mechanisms of regulation of the expression and catalytic activity of this essential enzyme. Experiments are designed to determine if iPLA2 activity is regulated by the accumulation of truncated forms of the protein that are encoded by alternatively spliced iPLA2 messages. These studies will focus on the cell cycle dependence of iPLA2 activity, as this is likely to have important implications for the accumulation of phospholipid mass for daughter cell membranes and potentially for the regulation of cell cycle progression. Among the studies to be performed are the quantification of full length and splice variant mRNAs and proteins at each phase of the cell cycle and the over expression of the splice variants to determine if this reduces the catalytic activity of endogenous iPLA2. Other experiments are focused on the potential regulation of iPLA2 expression by Sterol Response Element Binding Proteins (SREBP) and sterol metabolism. Several recent reports suggest that glycerophospholipid and sterol metabolism are coordinately regulated and preliminary experiments suggest that iPLA2 expression may be modulated by changes in sterol mass. To address this question, a putative Sterol Response Element (SRE) in the iPLA2 promoter will be characterized. In addition, experiments will be performed to determine if iPLA2 expression is induced in cells with low sterol content and if this is can be attributed to SREBP. Together these studies should provide important insights into the regulation of iPLA2 in mammalian cells. Given the essential role that iPLA2 plays in glycerophospholipid metabolism, these studies should provide information that is fundamental to our understanding of cell homeostasis. Cell membranes are largely composed of lipid molecules that until recently were thought to play a simple structural role in cell physiology. However, recent studies indicate that lipids have information content and can be broken down into other molecules that can regulate cell behavior. This research is intended to further our understanding of a critical enzyme, iPLA2, which regulates a subclass of lipids, the phospholipid molecules. As this enzyme controls the phospholipid content of cell membranes, it can have dramatic effects on both the integrity of a cell and its ability to respond to changes in its environment. These studies are designed to further elucidate mechanisms controlling both the amount of iPLA2 in cells (expression) and the functioning of the enzyme (activity). Together, these studies should provide insights into the regulation of an enzyme that plays a critical role in phospholipid metabolism. Given the importance of these molecules in controlling cell integrity and responsiveness, this information will be crucial to further our knowledge of how cells function.

甘油磷脂代谢的调节是细胞稳态的基础，因为这些分子在膜结构和细胞信号传导中都起着重要作用。最近的研究表明，80 kDa的钙非依赖性磷脂酶A2 （iPLA2）在磷脂代谢的调节中起着重要作用。本研究旨在进一步阐明该酶的表达和催化活性的调控机制。实验旨在确定iPLA2的活性是否受到由iPLA2信息拼接编码的蛋白质的截短形式的积累的调节。这些研究将集中在iPLA2活性的细胞周期依赖性上，因为这可能对子细胞膜磷脂质量的积累和细胞周期进程的潜在调节具有重要意义。即将进行的研究包括在细胞周期的每个阶段对全长和剪接变体mrna和蛋白质进行量化，以及剪接变体的过表达，以确定这是否会降低内源性iPLA2的催化活性。其他实验主要关注固醇反应元件结合蛋白（SREBP）和固醇代谢对iPLA2表达的潜在调控。最近的一些报道表明，甘油磷脂和固醇代谢是协调调节的，初步实验表明，iPLA2的表达可能受到固醇质量变化的调节。为了解决这个问题，我们将对iPLA2启动子中一个假定的甾醇反应元件（SRE）进行表征。此外，实验将确定iPLA2是否在低固醇含量的细胞中被诱导表达，以及这是否可归因于SREBP。总之，这些研究应该为哺乳动物细胞中iPLA2的调控提供重要的见解。鉴于iPLA2在甘油磷脂代谢中的重要作用，这些研究应该为我们理解细胞稳态提供基础信息。细胞膜主要由脂质分子组成，直到最近才被认为在细胞生理学中起着简单的结构作用。然而，最近的研究表明，脂质具有信息含量，可以分解成其他可以调节细胞行为的分子。这项研究旨在进一步加深我们对一种关键酶iPLA2的理解，iPLA2调节脂质亚类磷脂分子。由于这种酶控制着细胞膜的磷脂含量，它可以对细胞的完整性及其对环境变化的反应能力产生巨大影响。这些研究旨在进一步阐明控制细胞中iPLA2的数量（表达）和酶的功能（活性）的机制。总之，这些研究应该为在磷脂代谢中起关键作用的酶的调节提供见解。考虑到这些分子在控制细胞完整性和反应性方面的重要性，这些信息将对进一步了解细胞的功能至关重要。