Nuclear sphingolipid metabolism in regulation of myogenesis
核鞘脂代谢调节肌生成
基本信息
- 批准号:9437297
- 负责人:
- 金额:$ 25.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-05-15 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelApoptosisBindingBiochemicalBiochemical PathwayCell FractionationCell NucleusCell membraneCeramidaseCeramidesEnvironmentEnzymesFunctional disorderGene ExpressionGene TargetingGenerationsGenesGrowthHistone DeacetylaseHistone Deacetylase InhibitorHumanInvestigationLigandsLightLinkLipidsMembraneMetabolismModelingMuscleMuscular DystrophiesMyoblastsNeuromuscular DiseasesNuclearNuclear EnvelopeNuclear ProteinsNucleic Acid Regulatory SequencesPathologyPathway interactionsPeripheralPhysiological ProcessesProcessProductionProteinsRNA InterferenceRegulationRegulator GenesResearchRoleSignal TransductionSignaling MoleculeSphingolipidsSphingomyelinaseSphingosine-1-Phosphate ReceptorSubcellular FractionsTestingWorkceramide 1-phosphatechromatin immunoprecipitationimprovedinsightknock-downmyogenesissphingosine 1-phosphatesphingosine kinase
项目摘要
Sphingolipids (SLs) are essential structural components of membranes and provide reservoirs for critical
bioactive lipids, including ceramide and sphingosine 1-phosphate (S1P). Whereas ceramide is associated
with apoptosis and growth arrest, S1P commonly promotes survival and proliferation. The best-
characterized targets of S1P are S1P receptors localized to the plasma membrane. S1P also can act in
the nucleus by binding to and inhibiting class I histone deacetylases (HDACs), which are major regulators
of gene expression. SL signaling is characterized by highly compartmentalized generation and targeting of
the bioactive molecules. Substantial insight on localized S1P production and targeting at the plasma
membrane has been obtained, but little is known about regulation of SL metabolism in the nucleus. This
project involves investigation of proteins with potential roles in generating bioactive SLs in the nucleus.
The work includes analysis of a neutral sphingomyelinase localized to the nuclear envelope (NE) that is
required for myoblast differentiation, which may be integral to nuclear SL metabolism. This component and
other enzymes with potential links to nuclear SL metabolism will be analyzed in a cultured myoblast
differentiation model. Subcellular fractionation and lipidomics will be used to characterize the role of these
proteins in regulating the dynamic SL landscape of the nucleus during myoblast differentiation, and in
producing bioactive SLs including S1P. In addition, the potential functions of S1P in activating expression
of myogenic genes as an inhibitory ligand for class I HDACs will be evaluated. Overall this project will
investigate the hypothesis that the nucleus houses a distinctive SL metabolism that has a major role in
myogenic differentiation. The work has clear relevance to muscle pathology in humans, since HDAC
inhibitors including S1P have been shown to ameliorate muscular dystrophies in animal models.
鞘脂(SL)是膜的基本结构组分,并为关键的细胞膜提供储存库。
生物活性脂质,包括神经酰胺和1-磷酸鞘氨醇(S1 P)。而神经酰胺与
随着细胞凋亡和生长停滞,S1 P通常促进存活和增殖。最好的-
S1 P的特征性靶是定位于质膜的S1 P受体。S1 P也可以在
通过结合和抑制I类组蛋白脱乙酰酶(HDAC),这是主要的调节剂,
的基因表达。SL信号传导的特征在于高度区室化的产生和靶向
生物活性分子。对局部S1 P产生和靶向血浆的实质性见解
细胞膜上的SL代谢,但对细胞核内SL代谢的调控知之甚少。这
该项目涉及在细胞核中产生生物活性SL的潜在作用的蛋白质的研究。
这项工作包括分析定位于核膜(NE)的中性鞘磷脂酶,
成肌细胞分化所需的,这可能是不可或缺的核SL代谢。该部件和
将在培养的成肌细胞中分析与核SL代谢有潜在联系的其他酶
分化模型亚细胞分级和脂质组学将被用来表征这些作用,
在成肌细胞分化过程中调节细胞核动态SL景观的蛋白质,
产生包括S1 P的生物活性SL。此外,S1 P在激活表达中的潜在功能可能是
将评估肌源性基因作为I类HDAC的抑制性配体的作用。总体而言,该项目将
研究假设,即细胞核容纳一个独特的SL代谢,具有重要作用,
肌源性分化这项工作与人类的肌肉病理学有明显的相关性,因为HDAC
包括S1 P在内的抑制剂已经显示出改善动物模型中的肌营养不良。
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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Larry R. Gerace其他文献
Larry R. Gerace的其他文献
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{{ truncateString('Larry R. Gerace', 18)}}的其他基金
Mapping the organization of the peripheral nuclear compartment
绘制周围核区室的组织图
- 批准号:
9765209 - 财政年份:2015
- 资助金额:
$ 25.54万 - 项目类别:
Mapping the organization of the peripheral nuclear compartment
绘制周围核区室的组织图
- 批准号:
9326978 - 财政年份:2015
- 资助金额:
$ 25.54万 - 项目类别:
Mapping the organization of the peripheral nuclear compartment
绘制周围核区室的组织图
- 批准号:
9134119 - 财政年份:2015
- 资助金额:
$ 25.54万 - 项目类别:
Erlins in regulation of cholesterol-based endoplasmic reticulum functions
Erlins 调节基于胆固醇的内质网功能
- 批准号:
8111656 - 财政年份:2011
- 资助金额:
$ 25.54万 - 项目类别:
Erlins in regulation of cholesterol-based endoplasmic reticulum functions
Erlins 调节基于胆固醇的内质网功能
- 批准号:
8269809 - 财政年份:2011
- 资助金额:
$ 25.54万 - 项目类别:
IDENTIFICATION OF NET32 PROTEIN COMPLEXES FROM C2C12 CELLS
C2C12 细胞中 NET32 蛋白复合物的鉴定
- 批准号:
8171305 - 财政年份:2010
- 资助金额:
$ 25.54万 - 项目类别:
IDENTIFICATION OF DDX1 AND REV/RRE COFACTORS
DDX1 和 REV/RRE 辅因子的鉴定
- 批准号:
8171227 - 财政年份:2010
- 资助金额:
$ 25.54万 - 项目类别:
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