The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling

脂质转移蛋白调节的磷酸肌醇信号传导的生物学和生物化学

• 批准号: 9919592
• 负责人: Vytas A Bankaitis
• 金额: $ 68.27万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919592
• 关键词: Binding; Binding Proteins; Biodiversity; Biological; Biology; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cells; Chemicals; Code; Development; Disease; Eukaryota; Eukaryotic Cell; Experimental Models; Family member; G1 Phase; Goals; Golgi Apparatus; Individual; Inherited; Knowledge; Ligands; Link; Lipid Binding; Lipid Biochemistry; Lipids; Malignant Neoplasms; Mammals; Membrane; Molecular; Neocortex; Nerve Degeneration; Outcome; Phosphatidylinositols; Phospholipid Metabolism; Phosphotransferases; Physiological; Play; Protein Family; Protein Isoforms; Proteins; Research; Role; Signal Pathway; Signal Transduction; Specificity; Structure; System; Testing; Ursidae Family; Work; Yeasts; inorganic phosphate; interest; lipid metabolism; lipid transfer protein; member; nerve stem cell; nervous system disorder; novel strategies; oxysterol binding protein; paralogous gene; programs; trafficking

Abstract The large objective of the proposed research is to understand how eukaryotic cells organize major lipid signaling pathways, and how these do so in a manner that imparts both spatial and temporal specificity, and specificity of biological outcome. The system of interest is phosphoinositide signaling and the general question of how cells functionally channel a rather simple chemical code into a large diversity of biological activities. The experimental goal is to execute a detailed functional analysis of an underinvestigated class of proteins -- the phosphatidylinositol (PtdIns transfer proteins (PITPs) – who play a determining role in the functional channeling of PtdIns 4-OH kinase activities. To that end, two independent, but conceptually linked, directions will be pursued that: (i) exploit the prototypical member of the Sec14-superfamily and its five yeast paralogs as experimental models, and (ii) exploit development of the mammalian neocortex as physiological context with which to identify mechanisms of action of the three soluble mammalian PITP isoforms – the StART-like Class 1 PITPs – that are completely unrelated to the Sec14-like family of proteins in terms of structure. Both Sec14-like and StART-like PITPs are essential factors that operate at the interface of phospholipid metabolism and Golgi/ membrane signaling/trafficking functions. The proposed studies will test specific hypotheses that relate to: (i) how fungal and mammalian PITPs bind and exchange their lipid ligands, (ii) the mechanisms by which individual PITPs regulate specific steps of lipid metabolism in yeast and mammals (particularly neural stem cells and their progeny), and (iii) how the oxysterol binding protein (OSBP)-related proteins work against Sec14-dependent PtdIns-4-phosphate signaling in regulating Golgi PtdIns-4-P signaling and how this lipid binding protein antagonism is played out in control of cell cycle progression through the G1 phase of the cell cycle. These studies will clarify key unanswered questions regarding the mechanism of function of PITPs, the mechanisms by which both Sec14-like and StART-like PITPs couple lipid metabolism to PtdIns kinase signaling, and more global ramifications of PITP functional interactions with the oxysterol binding protein family members (ORPs). A growing number of inherited neurodegenerative and neurodevelopmental diseases, and diseases of proliferative disorders (e.g. cancer), are attributed to insufficiencies in Sec14-like and StART-like PITPs. Thus, the proposed studies will provide both new and fundamental information that bears directly on molecular mechanisms by which PITPs regulate and organize signal transduction in eukaryotes, and protect mammals from diseases of deranged cell proliferation and neurodegeneration.

抽象的 拟议研究的重大目标是了解真核细胞如何组织主要脂质 信号通路，以及如何以赋予空间和暂时特异性的方式进行这些操作，以及 生物学结果的特异性。感兴趣的系统是磷酸肌醇信号和一般 细胞如何在功能上将相当简单的化学代码引入大量生物学的问题 活动。实验目标是对未经研究的类别进行详细的功能分析 蛋白质 - 磷脂酰肌醇（PTDINS转移蛋白质（PITPS））在确定的作用 PTDINS 4-OH激酶活性的功能通道。为此，两个独立但概念性 链接的指示将提出：（i）利用Sec14-Superfamily及其的原型成员 五种酵母旁系同源物作为实验模型，（ii）将哺乳动物新皮质的开发作为 生理环境，以确定三种固体哺乳动物PITP的作用机理 同工型 - 类似开始的1类Pitps - 与Sec14样蛋白完全无关 就结构而言。 Sec14状和类似开始的坑都是在 磷脂代谢和高尔基/膜信号传导/运输功能的界面。提议 研究将检验与以下方面有关的特定假设：（i）真菌和哺乳动物pitps如何结合和交换 它们的脂质配体，（ii）单个PITP调节脂质代谢的特定步骤的机制 在酵母和哺乳动物（部分神经干细胞及其后代）中，以及（iii）氧蛋白酶结合如何 蛋白质（OSBP）相关蛋白在调节中对Sec14依赖性PTDINS-4-磷酸信号的作用 Golgi PTDINS-4-P信号传导以及该脂质结合蛋白拮抗作用如何在控制细胞周期中播放 通过细胞周期的G1阶段的进展。这些研究将阐明关键的未解决问题 关于PITP的功能机制，Sec14样和类似启动的机制 PITPS情侣脂质代谢对PTDINS激酶信号传导，以及PITP功能的全球影响 与氧蛋白酶结合蛋白家族成员（ORP）的相互作用。越来越多的继承 神经退行性和神经发育疾病以及增殖疾病（例如癌症）， 归因于Sec14状和类似开始的坑中的不足。这是拟议的研究将提供的 直接基于pitps的分子机制，新的和基本信息 调节和组织真核生物中的信号转导，并保护哺乳动物免受疾病的疾病 细胞增殖和神经退行性。