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: 0544068
• 负责人: Suzanne Barbour
• 金额: $ 58万
• 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: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0544068&HistoricalAwards=false
• 关键词: Regulation; Cell; Phospholipid; Metabolism; Phospholipase

Group VIA phospholipase A2 (iPLA2) is an enzyme that breaks down the lipids that comprise the membranes of mammalian cells. The enzyme has several important roles in cell biology, including regulating the amount of lipid available to make cell membranes, controlling the types of lipids in cell membranes, and regulating the production of biologically active lipids that allow cells to respond to changes in their environments. Recent evidence suggests that iPLA2 may also control the synthesis of cholesterol and the development of adipocytes (fat cells). These observations suggest that the effects of the enzyme are global and have impacts beyond the lipid metabolism of single cells. However, at present very little is known about the molecular mechanisms that control iPLA2 activity. The goal of this project is to delineate mechanisms controlling iPLA2 activity in mammalian cells. This project focuses on two mechanisms that control iPLA2 activity: alternative splicing and oligomerization. Alternative splicing refers to the concept that cells can generate different forms of iPLA2 that are active or inactive. Preliminary studies indicate that active iPLA2 enzymes may generate products that trigger the production of inactive forms of the enzyme that reduce activity. This may be an important feedback mechanism to control lipid metabolism in mammalian cells. Several iPLA2 proteins (monomers) must come together to form an active enzyme complex. Another aspect of this project is to determine how short (truncated) forms of iPLA2 prevent formation of active iPLA2 complexes and thereby suppress enzyme activity. Together, these studies will expand our knowledge of an essential homeostatic enzyme in cell lipid metabolism. The broader impact of this research is reflected in its potential to train the next generation of scientists and generate crucial knowledge concerning iPLA2 regulation and its influence on cellular and global lipid metabolism. Graduate students are directly involved in this research and have used experiments focused on the regulation of iPLA2 expression and/ or activity for their dissertation research. In addition, the project provides undergraduate students with technical training and insights into research as a career option. It also serves as a springboard for several outreach activities that are primarily focused on students at neighboring minority serving institutions (Virginia Union University, Virginia State University, and Hampton University). A more global impact of this project is its facilitation of the role of the Project Director as coordinator and participant in a seminar program that brings Virginia Commonwealth University researchers to the campuses of minority serving institutions. The overall goal of these activities is to contribute to the development of a pool of well-trained scientists and to ensure that the diversity of this pool reflects the public that it serves.

磷脂酶A2 （iPLA2）是一种分解构成哺乳动物细胞膜的脂质的酶。这种酶在细胞生物学中有几个重要的作用，包括调节可用于制造细胞膜的脂质数量，控制细胞膜中的脂质类型，以及调节生物活性脂质的产生，使细胞能够对环境的变化做出反应。最近的证据表明，iPLA2也可能控制胆固醇的合成和脂肪细胞（脂肪细胞）的发育。这些观察结果表明，酶的作用是全球性的，其影响超出了单个细胞的脂质代谢。然而，目前对控制iPLA2活性的分子机制知之甚少。本项目的目标是描述哺乳动物细胞中控制iPLA2活性的机制。本项目主要研究控制iPLA2活性的两种机制：选择性剪接和寡聚化。选择性剪接指的是细胞可以产生不同形式的活性或非活性iPLA2的概念。初步研究表明，活性iPLA2酶可能产生的产物会触发无活性iPLA2酶的产生，从而降低活性。这可能是控制哺乳动物细胞脂质代谢的重要反馈机制。几个iPLA2蛋白（单体）必须聚集在一起形成一个活性的酶复合物。该项目的另一个方面是确定短（截断）形式的iPLA2如何阻止活性iPLA2复合物的形成，从而抑制酶的活性。总之，这些研究将扩大我们对细胞脂质代谢中必需的稳态酶的认识。这项研究的广泛影响反映在其培养下一代科学家的潜力，并产生关于iPLA2调控及其对细胞和全球脂质代谢的影响的关键知识。研究生直接参与了这项研究，并在他们的论文研究中使用了专注于iPLA2表达和/或活性调控的实验。此外，该项目为本科生提供技术培训和对研究的见解，作为职业选择。它还作为几个扩展活动的跳板，主要关注邻近少数民族服务机构（弗吉尼亚联合大学、弗吉尼亚州立大学和汉普顿大学）的学生。这个项目的一个更大的全球影响是它促进了项目主任作为一个研讨会项目的协调员和参与者的角色，该研讨会项目将弗吉尼亚联邦大学的研究人员带到少数民族服务机构的校园。这些活动的总体目标是促进培养一支训练有素的科学家队伍，并确保这支队伍的多样性反映出它所服务的公众。