The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
批准号:
10386053
负责人:
Vytas A Bankaitis
金额:
$12.92万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-01 至 2024-04-30
关键词:
BindingBinding ProteinsBiodiversityBiologicalBiologyCell CycleCell Cycle ProgressionCell Cycle RegulationCell ProliferationCellsChemicalsCodeDevelopmentDiseaseEukaryotaEukaryotic CellExperimental ModelsFamily memberG1 PhaseGoalsGolgi ApparatusIndividualInheritedKnowledgeLigandsLinkLipid BindingLipid BiochemistryLipidsMalignant NeoplasmsMammalsMembraneMolecularNeocortexNerve DegenerationOutcomePhosphatidylinositolsPhospholipid MetabolismPhosphotransferasesPhysiologicalPlayProtein FamilyProtein IsoformsProteinsResearchRoleSignal PathwaySignal TransductionSpecificityStructureSystemTestingUrsidae FamilyWorkYeastsinorganic phosphateinterestlipid metabolismlipid transfer proteinmembernerve stem cellnervous system disordernovel strategiesoxysterol binding proteinparalogous geneprogramstrafficking
中文摘要
摘要
这项拟议研究的大目标是了解真核细胞如何组织主要脂肪。
信号通路,以及这些通路如何以赋予空间和时间特异性的方式做到这一点,以及
生物结果的特异性。感兴趣的系统是磷脂酰肌醇信号和一般
细胞如何在功能上将一个相当简单的化学密码导入到各种生物中的问题
活动。实验的目标是对一类未被调查的
蛋白质--磷脂酰肌醇(PtdIns Transfer Proteins,PITPs)--在
PtdIns 4-OH激酶活性的功能性通道。为此,两个独立的,但概念上
联系起来,将寻求以下方向:(1)利用Sec14-超级家族的原型成员及其
5个酵母菌作为实验模型,以及(Ii)利用哺乳动物新皮质的发育作为
识别三种可溶性哺乳动物PITP作用机制的生理背景
与Sec14-like蛋白家族完全无关的异构体--Start-like Class 1 PITPs
在结构方面。类Sec14和类Start的PITP都是在
磷脂代谢和高尔基体/膜信号/转运功能的接口。建议数
研究将检验与以下相关的具体假设:(I)真菌和哺乳动物的PITP如何结合和交换
它们的脂类配体,(Ii)个别PITP调节脂类代谢特定步骤的机制
在酵母和哺乳动物(特别是神经干细胞及其后代)中,以及(Iii)氧固醇如何结合
蛋白质(OSBP)相关蛋白在调节中对抗Sec14依赖的PtdIns-4-磷酸信号
高尔基体PtdIns-4-P信号转导机制及其在细胞周期调控中的作用
进入细胞周期的G1期。这些研究将澄清尚未回答的关键问题
关于PITPs的作用机制,Sec14样蛋白和Start样蛋白的机制
PITP将脂代谢与PtdIns激酶信号相结合,并对PITP功能的更多全球分支进行研究
与氧固醇结合蛋白家族成员(ORPs)的相互作用。越来越多的继承人
神经退行性疾病和神经发育疾病,以及增殖性疾病(如癌症),
归因于类Sec14和类Start的PITP的不足。因此,拟议的研究将提供
直接与PITPs的分子机制有关的新的和基本的信息
调控和组织真核生物的信号转导,保护哺乳动物免受错乱疾病的侵袭
细胞增殖和神经变性。
英文摘要
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.
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会议论文
The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
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批准号:10599878
-
项目类别:
-
资助金额:$68.49万
-
财政年份:2019
-
负责人:Vytas A Bankaitis
-
依托单位:
The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
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批准号:9919592
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项目类别:
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资助金额:$68.27万
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财政年份:2019
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负责人:Vytas A Bankaitis
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依托单位:
The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
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批准号:10392984
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项目类别:
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资助金额:$68.49万
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财政年份:2019
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负责人:Vytas A Bankaitis
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依托单位:
The Biology and Biochemistry of Lipid Transfer Protein-Regulated Phosphoinositide Signaling
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批准号:10797650
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资助金额:$16.4万
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依托单位:
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批准号:9063584
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项目类别:
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资助金额:$42.17万
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财政年份:2015
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负责人:Vytas A Bankaitis
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依托单位:
Functional Anatomy of Mammalian Phosphatidylinositol Transfer Proteins
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批准号:9262952
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项目类别:
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资助金额:$42.17万
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财政年份:2015
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负责人:Vytas A Bankaitis
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2011 Signal Transduction Within the Nucleus (Gordon Research Conference)
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批准号:8110200
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资助金额:$0.7万
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财政年份:2011
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负责人:Vytas A Bankaitis
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依托单位:
Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis
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批准号:8021812
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项目类别:
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资助金额:$27.19万
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财政年份:2008
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负责人:Vytas A Bankaitis
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依托单位:
Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis
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批准号:7763209
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项目类别:
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资助金额:$27.46万
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财政年份:2008
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负责人:Vytas A Bankaitis
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依托单位:
Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis
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批准号:7557880
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项目类别:
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资助金额:$27.74万
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财政年份:2008
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负责人:Vytas A Bankaitis
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依托单位:
Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis
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批准号:7303015
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项目类别:
-
资助金额:$27.74万
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负责人:Vytas A Bankaitis
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依托单位:
Core--BAC engineering technology
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批准号:6778902
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项目类别:
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资助金额:$13.1万
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财政年份:2003
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负责人:Vytas A Bankaitis
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依托单位:
Role of Mammalian PITP Beta in Neurodegenerative Disease
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批准号:6685909
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项目类别:
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资助金额:$30.92万
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财政年份:2001
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负责人:Vytas A Bankaitis
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依托单位:
Role of Mammalian PITP Beta in Neurodegenerative Disease
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批准号:6822586
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项目类别:
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资助金额:$34.37万
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财政年份:2001
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负责人:Vytas A Bankaitis
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依托单位:
Role of Mammalian PITP Beta in Neurodegenerative Disease
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批准号:6620338
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项目类别:
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资助金额:$30.92万
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财政年份:2001
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负责人:Vytas A Bankaitis
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依托单位:
Role of Mammalian PITP Beta in Neurodegenerative Disease
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批准号:6415767
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资助金额:$30.92万
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负责人:Vytas A Bankaitis
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财政年份:1998
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负责人:Vytas A Bankaitis
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依托单位:
Ptdins Transfer Protein Function and Neurodegeneration
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批准号:7038986
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Ptdins Transfer Protein Function and Neurodegeneration
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海外基金