Alcohol effect on Golgi morphology and function
酒精对高尔基体形态和功能的影响
基本信息
- 批准号:8679528
- 负责人:
- 金额:$ 11.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlcohol abuseAlcohol dehydrogenaseAlcoholic HepatitisAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholic liver damageAlcoholismAlcoholsAnimal FeedApoptosisApoptoticAsialoglycoprotein ReceptorAsialoglycoproteinsBindingCell DeathCell LineCell physiologyCellsCessation of lifeChronicClinicalComplexCoupledCytochrome P450Cytoplasmic TailDevelopmentDiseaseDockingEndoplasmic ReticulumEnzymesEthanolEventExcisionGoalsGolgi ApparatusGolgi TargetingGuanosine Triphosphate PhosphohydrolasesHealthHepatocyteHepatomegalyImpairmentIn VitroInduction of ApoptosisInjury to LiverLeadLigand BindingLiverLiver diseasesMediatingMembraneMorbidity - disease rateMorphologyMotorMusNonmuscle Myosin Type IIAPolysaccharidesPost-Translational Protein ProcessingProcessPropertyProtein GlycosylationProteinsRegulationReportingRoleStressStructureTestingalcohol abuse therapyalcohol effectalcohol exposurebasecaspase-3chronic alcohol ingestionfeedingglycosylationglycosyltransferasein vivoliver injurymacrogolginmortalitynew therapeutic targetnon-muscle myosinpreventproblem drinkerprotein transportretrograde transporttherapy developmenttrafficking
项目摘要
DESCRIPTION (provided by applicant): Chronic alcohol abuse and alcoholism are associated with high morbidity and mortality and known to cause major health problems such as alcoholic liver disease. Altered protein trafficking and glycosylation, and increased apoptosis have been reported in ethanol-exposed liver cells. But the mechanism remains unresolved. Recently, we found that non-muscle myosin IIA (NMIIA), a motor protein, interacts with the cytoplasmic tail of Golgi glycosyltransferases (GT) to induce Golgi fragmentation in cells under stress. The Golgi fragmentation was detected in hepatocytes exposed to alcohol in vitro and in vivo. Alcohol metabolites are responsible for this effect. Alcohol treatment also increases Rab6A GTPase, NMIIA, caspase-3 activity, NMIIA-GT complexes but decreases Golgi matrix protein, Giantin, and GT. In control cells, knockdown of Giantin retains GT in the endoplasmic reticulum. Knockdown of NMIIA or Rab6A prevents alcohol treatment- induced Golgi fragmentation. The results suggest that NMIIA and Rab6A are intimately involved in Golgi fragmentation induced by alcohol treatment. Further, the reduction of GT induced by alcohol treatment could be explained by (a) its elevated Golgi-to-endoplasmic reticulum retrograde transport forced by increased NMIIA-GT complexes coupled with (b) its impaired Golgi targeting resulted from elevated degradation of Giantin caused by activated caspase-3 activity. We propose to test the hypothesis that alcohol treatment- induced Golgi fragmentation is responsible for reduced glycosylation and function of asialoglycoprotein receptors as well as induction of apoptosis. The four specific aims of the proposed study are to: 1. Examine how during alcohol-specific Golgi fragmentation Rab6A regulates the interaction of NMIIA with GT followed by increased NMIIA-GT complexes; 2. Examine how elevated caspases-3 activity induced by alcohol treatment impairs ER-to-Golgi transport of GT; 3. Determine how the alcohol treatment-induced Golgi fragmentation affects glycan structure and function of asialoglycoprotein receptors including apoptosis; and 4. Validate the results of specific aims 1-3 obtained in VA-13 cells in the hepatocytes of alcohol-treated mice with and without functional asialoglycoprotein receptors. Accomplishment of the goal of the proposed study would expand our understanding of the regulation of cell death caused by ethanol abuse and help identify potential targets for developing therapy to treat alcoholic liver disease.
描述(由申请人提供):慢性酒精滥用和酒精中毒与高发病率和死亡率有关,并已知会引起重大健康问题,例如酒精性肝病。在暴露于乙醇的肝细胞中,蛋白质运输和糖基化的改变和凋亡增加。但是该机制仍未解决。最近,我们发现非肌肉肌球蛋白IIA(NMIIA)是一种运动蛋白,与高尔基糖基转移酶(GT)的细胞质尾巴相互作用,以在压力下诱导细胞中的高尔基体碎片化。在体外和体内暴露于酒精的肝细胞中检测到高尔基体碎片。酒精代谢物对此作用负责。酒精处理还增加了Rab6a GTPase,NMIIA,CASPASE-3活性,NMIIA-GT复合物,但降低了高尔基体基质蛋白,Giantin和GT。在对照细胞中,大蛋白的敲低保留在内质网中。 NMIIA或RAB6A的敲低可防止酒精治疗诱导的高尔基分裂。结果表明,NMIIA和RAB6A与酒精治疗引起的高尔基体碎裂密切相关。此外,酒精治疗诱导的GT的减少可以通过(a)其高尔基至胞质网状网状逆行转运升高,而NMIIA-GT复合物的增加,而NMIIA-GT复合物以及(b)其受损的高尔基靶向是由激活caspase-3导致的goiantin升级而导致的高尔基靶向。我们建议检验以下假设:酒精治疗诱导的高尔基体碎裂负责降低糖基化糖基化和肌瘤受体的功能以及凋亡的诱导。拟议的研究的四个具体目的是:1。检查在酒精特异性的高尔基体碎片中,Rab6a如何调节NMIIA与GT的相互作用,然后调节NMIIA-GT复合物的增加; 2。检查酒精治疗引起的caspase-3活性如何损害GT的ER到高尔基体的运输; 3。确定酒精治疗诱导的高尔基体碎片如何影响亚乳糖蛋白受体的聚糖结构和功能,包括凋亡;和4。验证在具有和不具有功能性亚乳糖糖蛋白受体的酒精治疗小鼠的肝细胞中VA-13细胞中获得的特定目标1-3的结果。实现拟议研究的目标将扩大我们对乙醇滥用引起的细胞死亡调节的理解,并有助于确定开发治疗酒精性肝病的潜在靶标。
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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Armen Petrosyan其他文献
Armen Petrosyan的其他文献
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{{ truncateString('Armen Petrosyan', 18)}}的其他基金
The role for alcohol-induced Golgi disorganization in the progression of prostate cancer
酒精引起的高尔基体紊乱在前列腺癌进展中的作用
- 批准号:
9816869 - 财政年份:2019
- 资助金额:
$ 11.32万 - 项目类别:
The role for alcohol-induced Golgi disorganization in the progression of prostate cancer
酒精引起的高尔基体紊乱在前列腺癌进展中的作用
- 批准号:
10223172 - 财政年份:2019
- 资助金额:
$ 11.32万 - 项目类别:
The role for alcohol-induced Golgi disorganization in the progression of prostate cancer
酒精引起的高尔基体紊乱在前列腺癌进展中的作用
- 批准号:
10675501 - 财政年份:2019
- 资助金额:
$ 11.32万 - 项目类别:
The role for alcohol-induced Golgi disorganization in the progression of prostate cancer
酒精引起的高尔基体紊乱在前列腺癌进展中的作用
- 批准号:
10459629 - 财政年份:2019
- 资助金额:
$ 11.32万 - 项目类别:
Alcohol effect on Golgi morphology and function
酒精对高尔基体形态和功能的影响
- 批准号:
8919185 - 财政年份:2014
- 资助金额:
$ 11.32万 - 项目类别:
Alcohol effect on Golgi morphology and function
酒精对高尔基体形态和功能的影响
- 批准号:
9127886 - 财政年份:2014
- 资助金额:
$ 11.32万 - 项目类别:
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