In vivo imaging to evaluate the effect of PUFAs on alcoholic fatty liver disease
体内成像评估多不饱和脂肪酸对酒精性脂肪肝的影响
基本信息
- 批准号:8835718
- 负责人:
- 金额:$ 4.27万
- 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:2014-09-16 至 2017-09-15
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAlcohol abuseAlcoholic Fatty LiverAlcoholic Liver CirrhosisAlcoholic Liver DiseasesAlcoholsAnimalsAttenuatedBiological AssayCause of DeathCell DeathCell ProliferationCellsCessation of lifeCirrhosisComplexConfocal MicroscopyDepositionDietDietary FatsDietary Fatty AcidDietary SugarsDiseaseEthanolEthanol MetabolismExtracellular MatrixFatty AcidsFatty LiverFatty acid glycerol estersFeeding behaviorsFibrosisFunctional disorderGenetic TranscriptionGuidelinesHealthHeartHeart DiseasesHepaticHepatic Stellate CellHepatocyteHigh Pressure Liquid ChromatographyHumanImageryIn Situ HybridizationInflammationInflammatoryInjuryInvestigationKnowledgeKupffer CellsLabelLarvaLeadLifeLipidsLiverLiver CirrhosisLiver FailureLiver FibrosisLiver diseasesMetabolicMetabolismMethodsMitochondriaModelingMovementNatureObesityOrganOxidative StressPathogenesisPatientsPhospholipidsPolyunsaturated Fatty AcidsPopulationPrimary carcinoma of the liver cellsProceduresProcessProliferatingProtein SecretionRoleSaturated Fatty AcidsSeriesSeveritiesSignal TransductionSteatohepatitisStressSymptomsTestingTissuesTransgenic OrganismsTriglyceridesTumor Necrosis Factor-alphaUnited StatesWorkZebrafishalcohol effectalcohol responsebody systemcell behaviorcell typecellular imagingcytokinefeedingin vivoin vivo imaginglipid metabolismliver inflammationliver injurymacrophageproblem drinkerresponseresponse to injurystressortoll-like receptor 4
项目摘要
DESCRIPTION (provided by applicant): Cirrhosis is characterized by advanced steatosis, fibrosis, and inflammation of the liver that often leads to liver failure, can progress to hepatocellular carcinoma, and is the twelfth leading cause of death in the United States. Alcoholic cirrhosis is thought to develop through repeated activation of the acute hepatic injury response: ethanol or another stressor activates Kupffer cells (liver-specific macrophages), which signal hepatic stellate cells to proliferate and overproduce extracellular matrix, eventually leading to fibrosis. Although the role of alcohol overconsumption alone in determining the long-term progression of liver disease has been studied extensively, the acute hepatic injury response to alcohol and how it is influenced by fat stored in hepatocytes and consumed in the diet is not well understood. Lipotoxicity, in which lipids stored in non-adipose tissues promote cell dysfunction and death, has been documented in multiple human organ systems and tissues, but is not well characterized in the liver. I hypothesize that dietary polyunsaturated fatty acids (PUFAs), already know to protect against lipotoxicity-induced cell death in the heart when compared with dietary saturated fatty acids and to attenuate inflammation by suppressing signaling through the TLR4 receptor, will protect against steatohepatitis by mitigating the inflammatory effects of alcohol. Larval zebrafish will serve as a model for investigation of how the presence of alcohol affects the metabolism of dietary lipids, and the role of diet composition in alcoholic liver injury. To this end I have optimized an ethanol treatment procedure that results
in a significant increase in hepatic lipid content without affecting feeding behavior. I have also developed HPLC methods that will be used to analyze whole-body triglyceride and phospholipid composition of zebrafish larvae treated with ethanol and given a range of diets with varying fatty acid content. Liver injury will be assayed using qRT-PCR and in situ hybridization for inflammatory cytokines, immunostaining for fibrosis, and live imaging of the cell populations involved in the hepatic injury response in several fluorescent transgenic zebrafish lines.
描述(由申请人提供):肝硬化的特征是晚期脂肪变性,纤维化和肝脏的炎症通常导致肝衰竭,可以发展为肝细胞癌,并且是美国第十二个主要死亡原因。人们认为,酒精性肝硬化是通过反复激活急性肝损伤反应而发展的:乙醇或其他胁迫激活kupffer细胞(肝脏特异性巨噬细胞),这表明肝肝星状细胞增殖和过度产生细胞外基质,最终导致纤维化。尽管已经对酒精过度消费在确定肝病的长期进展中的作用进行了广泛的研究,但对酒精的急性肝损伤反应以及如何受到肝细胞中储存并在饮食中食用的脂肪的影响。在多个人体器官系统和组织中已记录了脂肪毒性,其中脂质储存在非脂肪组织中的脂质促进了细胞功能障碍和死亡,但在肝脏中并未得到很好的特征。我假设与饮食饱和饱和脂肪酸相比,已经知道可以预防脂肪毒性诱导的细胞死亡的饮食多不饱和脂肪酸(PUFAS),并通过通过TLR4受体来抑制信号来减轻炎症,将通过炎症性的炎性效应来防止steatohohepatitor。幼虫斑马鱼将作为研究酒精的存在如何影响饮食脂质的代谢以及饮食组成在酒精性肝损伤中的作用的模型。为此,我优化了乙醇治疗程序
在不影响喂养行为的情况下,肝脂质含量的显着增加。我还开发了HPLC方法,该方法将用于分析用乙醇处理的斑马鱼幼虫的全身甘油三酸酯和磷脂组成,并给予一系列脂肪酸含量不同的饮食。肝损伤将使用QRT-PCR和原位杂交进行炎性细胞因子,免疫染色以进行纤维化,并在几种荧光转基因斑马鱼线中对参与肝损伤反应的细胞种群进行实时成像。
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)
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Vanessa Helen Quinlivan-Repasi其他文献
Vanessa Helen Quinlivan-Repasi的其他文献
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{{ truncateString('Vanessa Helen Quinlivan-Repasi', 18)}}的其他基金
In vivo imaging to evaluate the effect of PUFAs on alcoholic fatty liver disease
体内成像评估多不饱和脂肪酸对酒精性脂肪肝的影响
- 批准号:
8927328 - 财政年份:2014
- 资助金额:
$ 4.27万 - 项目类别:
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