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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要