Directing Membrane Function with Inositol Lipids in Health and Disease
在健康和疾病中用肌醇脂质指导膜功能
基本信息
- 批准号:10532152
- 负责人:
- 金额:$ 46.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:Adverse effectsAffectCell Culture TechniquesCell Membrane PermeabilityCell membraneCellsCoupledCouplesCouplingCytoskeletonDependenceDiseaseExcisionFailureFoundationsFundingGeneticGoalsHealthIndividualInositolKnowledgeLifeLipidsMalignant NeoplasmsMembraneMendelian disorderMetabolismMissionMitochondriaMolecularNational Institute of General Medical SciencesOrganellesOrganismPIK3CG genePathogenesisPathogenicityPhosphatidylinositolsPhosphoric Monoester HydrolasesPhysiological ProcessesPreventionProcessProteinsPublic HealthRegulationResearchSignal TransductionSpecificityTherapeuticTherapeutic InterventionTimeUnited States National Institutes of Healthdisease phenotypegenetic manipulationhuman diseaselipid transfer proteinneoplasticphosphoinositide-3,4-bisphosphatepreventprotein activationreceptorrecruitspatiotemporalsynthetic biologytool
项目摘要
PROJECT SUMMARY/ABSTRACT
The plasma membrane (PM) is a bustling hub of transport, signaling and structural functions that sustain life at
the cellular level. Failure to appropriately choreograph these parallel functions contributes to the pathogenesis
of many diseases. Selective regulation of PM function relies on the cytosolic leaflet phosphoinositide (PPIn) lipid,
phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. PI(4,5)P2 is a master regulator, recruiting and/or activating
scores of proteins controlling PM permeability, vesicular traffic, cytoskeletal assembly and receptor-driven
signaling. Human diseases from cancer to rare monogenic disorders are known to be associated with aberrant
PI(4,5)P2 levels, which result from disrupted PI(4,5)P2 synthesis or breakdown. That said, the sheer number of
PI(4,5)P2-regulated functions has made it challenging to identify which functions contribute to disease
phenotype, let alone attempt therapeutic intervention. Therefore, the long-term goal of the lab's research is to
develop a detailed, mechanistic understanding of how PPIn metabolism couples to individual physiological
processes; ultimately, we aim to use this knowledge to develop strategies that modulate or restore PI(4,5)P2
regulation of individual functions that are aberrant in disease. Our goal in this application is to define three
distinct mechanisms by which metabolism of PM PI(4,5)P2 or its signaling products couple to multiple
physiological processes. In the first project, we leverage our recent discovery of a PM PI(4,5)P2 homeostatic
mechanism to experimentally tune the lipid level in cells: this will allow us for the first time to determine the
PI(4,5)P2 concentration-dependence of key PM functions. This will reveal which functions are most affected by
pathogenic PI(4,5)P2 levels and thus likely drive disease phenotypes – a crucial first step in devising therapeutic
interventions. In the second project, we will identify lipid transfer proteins (LTPs) that couple PPIn removal from
membranes to their degradation by PPIn phosphatases located in other organelles. We will employ a synthetic
biology approach in which LTPs deplete ectopic mitochondrial PPIn in live cells. Identifying LTPs coupled to
different PPIn pools will reveal new targets to prevent PPIn accumulation in monogenic disease where
phosphatase activity is lost. In the third project, we will define the distinct PI3K signaling landscapes driven by
the two downstream lipid products of PI(4,5)P2: PIP3 and PI(3,4)P2. We will define the unique spatiotemporal and
effector protein activation profiles of these lipids in live cells, using our unique molecular tools to precisely detect
and chemogenetically manipulate the lipids in cell culture. Crucially, this will identify spatiotemporal and effector
protein activation profiles that are unique to each lipid. This knowledge will be vital to eliminate on-target adverse
effects of proven PI3K therapeutics. Collectively, at the conclusion of this funding cycle we expect to have defined
fundamental principles by which specificity emerges from the coupling of PM PI(4,5)P2 signaling to individual PM
functions in cells. This will be significant, because it will provide the conceptual framework for experimental and
eventually therapeutic intervention in these isolated processes at the point of PI(4,5)P2 regulation.
项目总结/摘要
质膜(PM)是维持生命的运输,信号和结构功能的繁忙枢纽,
细胞水平。未能适当地设计这些平行功能有助于发病机制
许多疾病。PM功能的选择性调节依赖于胞质小叶磷酸肌醇(PPIn)脂质,
磷脂酰肌醇4,5-二磷酸[PI(4,5)P2]。PI(4,5)P2是主调节因子,募集和/或激活
控制PM渗透性、囊泡运输、细胞骨架组装和受体驱动的蛋白质的分数
发信号。从癌症到罕见的单基因疾病的人类疾病已知与异常的基因表达相关。
PI(4,5)P2水平,其由PI(4,5)P2合成或分解中断引起。也就是说,
PI(4,5)P2调节的功能使得识别哪些功能有助于疾病变得具有挑战性
表型,更不用说尝试治疗干预。因此,该实验室研究的长期目标是
发展一个详细的,机械的了解PPin代谢如何夫妇个人的生理
过程;最终,我们的目标是利用这些知识来制定调节或恢复PI(4,5)P2的策略
调节疾病中异常的个体功能。我们在这个应用程序中的目标是定义三个
PM PI(4,5)P2或其信号传导产物的代谢通过不同的机制与多个细胞偶联。
生理过程。在第一个项目中,我们利用我们最近发现的PM PI(4,5)P2稳态
通过实验调节细胞中脂质水平的机制:这将使我们能够首次确定
关键PM功能的PI(4,5)P2浓度依赖性。这将揭示哪些功能受影响最大
致病性PI(4,5)P2水平,从而可能驱动疾病表型-设计治疗方案的关键第一步
干预措施。在第二个项目中,我们将确定脂质转移蛋白(LTP),将PPIn从
膜的降解PPIn磷酸酶位于其他细胞器。我们将使用一种合成的
LTP消耗活细胞中异位线粒体PPIn的生物学方法。识别耦合到
不同的PPIn库将揭示新的靶点,以防止PPIn在单基因疾病中的积累,
磷酸酶活性丧失。在第三个项目中,我们将定义由以下因素驱动的不同PI 3 K信号环境:
PI(4,5)P2的两种下游脂质产物:PIP 3和PI(3,4)P2。我们将定义独特的时空和
这些脂质在活细胞中的效应蛋白激活谱,使用我们独特的分子工具精确检测
并在细胞培养物中化学遗传地操纵脂质。至关重要的是,这将确定时空和效应器
每种脂质所特有的蛋白质活化谱。这些知识对于消除靶向不良反应至关重要。
证明PI 3 K疗法的效果。总的来说,在本供资周期结束时,我们预计将确定
特异性从PM PI(4,5)P2信号传导与个体PM的偶联中出现的基本原理
细胞中的功能。这将很重要,因为它将为实验和研究提供概念框架。
最终在PI(4,5)P2调节点对这些孤立过程进行治疗性干预。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gerald R Hammond其他文献
Gerald R Hammond的其他文献
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{{ truncateString('Gerald R Hammond', 18)}}的其他基金
PIP5K1A as a novel driver of PI3K signaling in health and disease
PIP5K1A 作为健康和疾病中 PI3K 信号传导的新型驱动因素
- 批准号:
10214915 - 财政年份:2021
- 资助金额:
$ 46.39万 - 项目类别:
Directing Membrane Function with Inositol Lipids in Health and Disease
在健康和疾病中用肌醇脂质指导膜功能
- 批准号:
10330117 - 财政年份:2016
- 资助金额:
$ 46.39万 - 项目类别:
Directing membrane function with inositol lipids in health and disease
在健康和疾病中用肌醇脂质指导膜功能
- 批准号:
9978831 - 财政年份:2016
- 资助金额:
$ 46.39万 - 项目类别:
Directing membrane function with inositol lipids in health and disease
在健康和疾病中用肌醇脂质指导膜功能
- 批准号:
9135008 - 财政年份:2016
- 资助金额:
$ 46.39万 - 项目类别:
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