Effects of cellular lipid droplet allocation on lipid droplet consumption and Drosophila embryogenesis
细胞脂滴分配对脂滴消耗和果蝇胚胎发生的影响
基本信息
- 批准号:10200107
- 负责人:
- 金额:$ 4.6万
- 依托单位:
- 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:2019-07-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active Biological TransportAddressAffectAnimalsAreaBiologyBlastodermCell Culture SystemCell Culture TechniquesCellsCellular biologyComplexConsumptionCultured CellsDataDepositionDevelopmentDevelopmental Delay DisordersDiseaseDrosophila genusEmbryoEmbryonic DevelopmentEnergy IntakeEnergy SupplyEnergy-Generating ResourcesFatty LiverFatty acid glycerol estersFertilizationGeneticGoalsGrowthKnock-outLinkLipaseLipidsLipolysisLiver diseasesMammalian CellMammalsMediatingMedicalMetabolicMetabolismMicrotubulesMitochondriaMotorMusNon-Insulin-Dependent Diabetes MellitusNutrientNutritional statusObesityOrganellesOrganismPositioning AttributePropertyProteinsRegulationResearchRoleStarvationStructureSystemTestingTimeToxic effectTriglyceridesbaseblastomere structureexperienceflyhatchinghuman diseaselipid metabolismlipid transportmutantpreventresponsetool
项目摘要
Lipid droplets have recently emerged as an exciting, disease relevant topic of research. Droplet biology is
intrinsically linked to fat metabolism, which is in turn linked to a multitude of human diseases despite the
obvious medical importance of lipid droplets, much of their cellular biology is poorly understood. It has recently
become clear that throughout the animal kingdom lipid droplets are transported within the cell. It appears that
the cellular region a lipid droplet is positioned to affects its metabolic state allowing cells to transport droplets
into a ‘degradative region’ when starved or a ‘growth region’ when fed. Testing this hypothesis and examining
the overall importance of lipid droplet allocation in the developmental system of the Drosophila embryo is the
goal of this proposal. It is the Drosophila embryo where our mechanistic understanding of how lipid droplets
are transported is the most advanced. While the impetus of previous such research was to understand general
properties of active transport, I will now employ this system to droplet biology. The decades of transport driven
research done by our lab has yielded a vast repertoire of genetic tools which I plan to utilize to interrogate the
role transport mediated lipid droplet allocation between embryonic cells. My preliminary data shows that
disrupting proper transport of lipid droplets along microtubules diminishes turnover of triglycerides (stored in
lipid droplets) and may cause a delay in embryonic development. Intriguingly, droplet consumption because of
improper intracellular positioning fits nicely with data gathered from mammalian systems: mouse embryos
extensively reposition their lipid droplets post fertilization and mammalian cultured cells use microtubules to
reposition droplets depending on nutritional status. These strong similarities between mammals and flies not
only suggests conservation of transport mediated positioning of lipid droplets across taxa, but also supports the
notion that lipid droplet positioning itself may be a means regulating cellular lipid metabolism. I will test this at
an organismal level. This proposal aims to address why loss of lipid droplet based active transport impedes
their consumption and how that that failed consumption would then delay embryonic development. It seems
likely that improperly allocating droplets would cause a state of relative starvation in droplet-deprived cells.
Mammalian cell culture system have elucidated several markers of cellular lipid starvation which I will examine
in these lipid droplet deprived embryos. Next, the delay in embryogenesis is likely caused by diminished
droplet consumption at the embryonic level which would globally diminish the energy supply. To pin this down,
I will use a panel of genetic mutants, which fail in lipid droplet allocation to varying degrees, to extrapolate the
relationship between failed lipid droplet consumption and delayed embryogenesis. These studies would
constitute strong support of the role of lipid-droplet-transport-mediated cellular allocation and its
importance for development.
脂滴最近成为一个令人兴奋的、与疾病相关的研究课题。
与脂肪代谢有着内在的联系,而脂肪代谢又与多种人类疾病有关,尽管
尽管脂滴的医学重要性显而易见,但人们对它们的许多细胞生物学知之甚少。
很明显,在整个动物界中,脂滴似乎在细胞内运输。
细胞区域中脂滴的位置会影响其代谢状态,使细胞能够运输脂滴
饥饿时进入“退化区域”,进食时进入“生长区域”。
脂滴分配在果蝇胚胎发育系统中的总体重要性是
该提案的目标是在果蝇胚胎中我们了解脂滴的机制。
运输是最先进的,而以前此类研究的动力是了解一般性。
主动运输的特性,我现在将利用这个系统来滴落生物学的数十年。
我们实验室所做的研究已经产生了大量的遗传工具,我计划利用它们来探究
我的初步数据表明,运输介导胚胎细胞之间的脂滴分配。
破坏脂滴沿着微管的正常运输会减少甘油三酯的周转(储存在
有趣的是,由于液滴消耗,可能会导致胚胎发育延迟。
不正确的细胞内定位与从哺乳动物系统收集的数据非常吻合:小鼠胚胎
通常在受精后重新定位其脂滴,哺乳动物培养细胞使用微管
根据营养状况重新定位液滴,哺乳动物和苍蝇之间的这些强烈相似之处并非如此。
只表明运输介导的脂滴跨类群定位的保守性,但也支持
我认为脂滴定位本身可能是调节细胞脂质代谢的一种手段。
该提案旨在解决为什么基于脂滴的主动运输会受到阻碍。
他们的消费以及失败的消费似乎会延迟胚胎发育。
不正确的液滴分配可能会导致液滴剥夺的细胞处于相对饥饿的状态。
哺乳动物细胞培养系统已经阐明了细胞脂质饥饿的几种标志物,我将对其进行检查
接下来,在这些脂滴被剥夺的胚胎中,胚胎发生的延迟可能是由减少引起的。
在胚胎水平上的液滴消耗将在全球范围内减少能源供应。
我将使用一组基因突变体来推断,这些突变体在脂滴分配上有不同程度的失败。
这些研究将揭示脂滴消耗失败与胚胎发生延迟之间的关系。
有力支持了脂滴转运介导的细胞分配及其作用
对发展的重要性。
项目成果
期刊论文数量(0)
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Marcus Daniel Kilwein其他文献
Marcus Daniel Kilwein的其他文献
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{{ truncateString('Marcus Daniel Kilwein', 18)}}的其他基金
Effects of cellular lipid droplet allocation on lipid droplet consumption and Drosophila embryogenesis
细胞脂滴分配对脂滴消耗和果蝇胚胎发生的影响
- 批准号:
10056973 - 财政年份:2019
- 资助金额:
$ 4.6万 - 项目类别:
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