Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
基本信息
- 批准号:6823169
- 负责人:
- 金额:$ 21.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-07-15 至 2008-06-30
- 项目状态:已结题
- 来源:
- 关键词:cystathionine beta synthasedietary aminoaciddietary proteinsdietary supplementsenzyme activitygene expressiongenetic transcriptionhigh performance liquid chromatographylaboratory ratnorthern blottingsnuclear runoff assaynutrient interactionnutrition related tagoxidative stresspolymerase chain reactionposttranslational modificationsprotein glutamine gamma glutamyltransferaseprotein quantitation /detectiontissue /cell culturetranscription factorwestern blottings
项目摘要
DESCRIPTION (provided by applicant): The rate-limiting enzyme for glutathione (GSH) synthesis is gamma-glutamylcysteine synthetase (GCS). Despite much study over the past two decades, the molecular and signaling mechanisms involved in regulation of GCS activity in cells are still poorly understood. Nutrient-induced regulation of GCS gene expression has not been reported except for preliminary work done in our laboratory over the past few years. Our long-term goal is to elucidate the mechanisms by which dietary sulfur amino acid or protein level induces changes in levels of the two subunits of GCS and changes in GCS activity state as well as the role of cellular cysteine status in this process. Specific objectives of this project are: (1) to determine the effect of cysteine supplementation on the expression of the modifier subunit of GCS and to determine the effect of cysteine supplementation on the ratio of the catalytic and modifier subunits in liver cells; (2) to determine the effect of dietary protein and sulfur amino acid supplementation on the expression of the modifier subunit of GCS and the ratio of the catalytic and modifier subunits of GCS in liver of intact rats; (3) to determine if the level of the GCS modifier subunit is limiting for GCS holoenzyme formation in HepG2 cells; (4) to determine the roles of GCS gene transcription and message stability in regulation of GCS subunit mRNA levels in response to cysteine concentration; (5) to determine if GCS subunit degradation rates are regulated; (6) to assess the ability of cysteine analogs (esp. cysteamine) to downregulate GCS subunit expression and/or GCS activity; (7) to determine if expression of GCS subunit genes and GCS activity are regulated in response to cysteine concentration vs. GSH concentration or thiol/disulfide redox state; and (8) to determine if transcription factor Nrf2 is necessary for activation of GCS subunit gene transcription. Capacity for GSH synthesis, availability of the precursor amino acid cysteine, and steady-state GSH levels all contribute to the body's ability to defend itself against oxidative or chemical stressors.
描述(申请人提供):谷胱甘肽(GSH)合成的限速酶是γ-谷氨酰半胱氨酸合成酶(GCS)。尽管在过去的二十年里进行了大量的研究,但涉及细胞内GCS活性调节的分子和信号机制仍然知之甚少。除了我们实验室在过去几年中所做的前期工作外,营养诱导对GCS基因表达的调控尚未见报道。我们的长期目标是阐明日粮含硫氨基酸或蛋白质水平引起GCS两个亚单位水平变化和GCS活性状态变化的机制,以及细胞半胱氨酸状态在这一过程中的作用。本项目的具体目标是:(1)测定半胱氨酸补充对GCS修饰亚基表达的影响,以及半胱氨酸补充对肝细胞GCS催化亚基和修饰亚基比例的影响;(2)测定补充蛋白质和含硫氨基酸对正常大鼠肝脏GCS修饰亚基表达和催化亚基与修饰亚基比例的影响;(3)确定GCS修饰亚基水平是否限制了HepG2细胞GCS全酶的形成;(4)确定GCS基因转录和信息稳定性在半胱氨酸浓度对GCS亚单位mRNA水平调节中的作用;(5)确定GCS亚单位降解率是否受到调节;(6)评估半胱氨酸类似物(特别是。目的:(1)确定GCS亚单位基因转录是否受半胱氨酸浓度的影响;(2)半胱胺)下调GCS亚单位表达和/或GCS活性;(7)确定GCS亚单位基因的表达和GCS活性是否受半胱氨酸浓度与GSH浓度或硫醇/二硫键氧化还原状态的影响;以及(8)确定转录因子Nrf2是否是激活GCS亚单位基因转录所必需的。GSH合成的能力、前体氨基酸半胱氨酸的可获得性以及稳定的GSH水平都有助于人体抵御氧化或化学应激的能力。
项目成果
期刊论文数量(0)
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MARTHA H STIPANUK其他文献
MARTHA H STIPANUK的其他文献
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{{ truncateString('MARTHA H STIPANUK', 18)}}的其他基金
Cross-talk between GCN2 and mTOR in integration of nutrient signaling
GCN2 和 mTOR 在营养信号整合中的串扰
- 批准号:
7847735 - 财政年份:2009
- 资助金额:
$ 21.74万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
7251533 - 财政年份:2004
- 资助金额:
$ 21.74万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
6919340 - 财政年份:2004
- 资助金额:
$ 21.74万 - 项目类别:
Nutritional Regulation of y-Glutamylcysteine Synthetase
γ-谷氨酰半胱氨酸合成酶的营养调节
- 批准号:
7082073 - 财政年份:2004
- 资助金额:
$ 21.74万 - 项目类别: