Biliary oxysterols and cholangiocarcinoma
胆汁氧甾醇和胆管癌
基本信息
- 批准号:7216874
- 负责人:
- 金额:$ 21.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:AmericanAmerican IndiansAnchorage-Independent GrowthApoptosisAreaAsiansAutopsyBacteriaBacterial InfectionsBehaviorBile fluidBiliaryBiliary calculiBiochemicalBiochemical ReactionBiologicalBiological ProcessCalculiCancer cell lineCanis familiarisCarcinogenesis MechanismCaucasiansCaucasoid RaceCell ProliferationCell membraneCellsCellular MorphologyCellular biologyCharacteristicsChileChinese PeopleCholangiocarcinomaCholangitisCholelithiasisCholesterolChronicClinicalConditionDiseaseEnzymesEpidemiologyEpithelialEpithelial CellsEpitheliumEtiologyEventExhibitsExposure toFrequenciesGallbladderGallbladder CarcinomaGrowthHigh Pressure Liquid ChromatographyHumanIn VitroIncidenceInfectionInflammatoryIntrahepatic CholangiocarcinomaKineticsLeukocytesLipidsLong-Term EffectsMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of gallbladderMapsMass Spectrum AnalysisMediatingMembrane MicrodomainsMetabolismMethodologyMicrobial BiofilmsMitogen-Activated Protein KinasesModelingMolecularMolecular BankMolecular and Cellular BiologyMorphologyMucinsMummiesNative AmericansNude MiceOryctolagus cuniculusPathologic ProcessesPathway interactionsPatientsPhysical ChemistryPhysiologyPopulationPrevalencePreventionProcessProductionProstaglandin-Endoperoxide SynthaseRaceRecurrenceSamplingSignal Transduction PathwaySiteSouth American IndiansSterilitySterolsStructural BiochemistryStructureSumSurfaceTechniquesTimeUnited States National Institutes of HealthWorkbiliary tractcarcinogenesiscell growthcyclooxygenase 1designexperiencein vivoinsightinterdisciplinary approachintrahepaticmortalityoxidationprimary sclerosing cholangitisrepositoryresearch studyresponsetumor
项目摘要
There is a worldwide and steady increase in the incidence of cholangiocarcinoma, a malignancy with very
limited treatment options and high mortality. This expecially involves racial groups where the prevalence of biliary
stones are high - such as Native Americans, South American Indians, andAsians. Of all the etiologic factors,
cancers of the gallbladder and the biliary tree are most highly correlated with the presence of biliary stones, and
chronic bacterial infection. We have recently discovered that in patients with gallbladder and intrahepatic stones,
which are almost always covered by a bacterial biofilm, that there are oxidzed products of cholesterol. Two of
these oxysterol species have been unequivocally identified. The presence and abundance of oxysterols in human
bile and gallstones correlated with the presence of bacterial infection, and with the amount of bacterial DMA
present in the stones. Oxysterols, on short term exposure to biliary epithelial cells, exhibit profound effects on
apoptosis, cell proliferation, mucin synthesis and secretion. With long term exposure, dog gallbladder epithelial
exhibited features characteristic of malignant transformation.
We hypothesize that biliary oxysterols originate from endogenous biliary cholesterol as a result of oxidation from
leukocytic enzymes in bacterial-leukocyte interactions. In addition, oxysterols mediate inflammatory and malignant
transformation of biliary epithelial cells. We also hypothesizethat the molecular mechanism of oxysterol induced
carcinogenesis to mediate through lipid microdomains (rafts).
The Specific AimsTof this proposal are: 1) To determine the origin of biliary' bxysJerol.'We propose in vitro '
experiments using human leukocytes and model bile, as well,as in vivo experiments using a rabbit model with
controlled induction of bacterial infection. The1 kinetics ofioxysterol production, the intermediates and the products
wilhbe determined 2a) To construct a1 molecular library of;the;composition and structural identity of the oxidative
products of cholesterol in hurpan bile'using high perforirfancdjiiiquidilchromatography (HPLC), interfacing,,with '''ij':^ j
mass spectometry (MS) and, IMS/MS. 2$),To characterize'ithe'physicpchemical and biological function of'these ;|y', |
oxysterols. 3) To use oxysterol in long-term co-cultur;e with normal human biliary (gallbladder) epithelial cells to'''/1
induce carciongenesis. Cell morphology/cancerjgrqwth pathways wiil.'be determined before,' du'ringiand after V
cancer formation., _ __, 'jfv \t\ '¿, V'1' 'li'i !!'' JU'H . . '¿!;! :!''<'.! i"V ¿ ,'i1. ¿.!
this proposal uses a multidisciplinary approach including structural biochemistry, cell and molecular biology,
and physical chemistry methodologies. It promises to open up a new area of biliary physiology and metabolism;
create a molecular library for cholesterol oxidation products in humans; add new and important understanding and
insight into the etiology of cholangiocarcinoma; and guide strategic treatment and prevention of this important and
vexinq disease.
胆管癌是一种非常常见的恶性肿瘤,其发病率在世界范围内稳步上升。
治疗选择有限且死亡率高。这尤其涉及胆道疾病患病率较高的种族群体
石头高——比如美洲原住民、南美印第安人和亚洲人。在所有的病因因素中,
胆囊癌和胆道树癌与胆道结石的存在高度相关,并且
慢性细菌感染。我们最近发现,在胆囊和肝内结石患者中,
它们几乎总是被细菌生物膜覆盖,其中存在胆固醇的氧化产物。两个
这些氧甾醇种类已被明确鉴定。人体中氧甾醇的存在和丰度
胆汁和胆结石与细菌感染的存在以及细菌 DMA 的量相关
存在于石头中。氧甾醇在短期暴露于胆道上皮细胞时,对胆管上皮细胞表现出深远的影响。
细胞凋亡、细胞增殖、粘蛋白合成和分泌。长期接触,狗的胆囊上皮细胞
表现出恶变的特征。
我们假设胆汁氧甾醇源自内源性胆汁胆固醇,是氧化的结果。
细菌-白细胞相互作用中的白细胞酶。此外,氧甾醇介导炎症和恶性
胆管上皮细胞的转化。我们还假设氧甾醇诱导的分子机制
通过脂质微结构域(筏)介导致癌作用。
该提案的具体目标是: 1) 确定胆道“bxysJerol”的起源。“我们建议在体外”
使用人类白细胞和模型胆汁进行的实验,以及使用兔模型进行的体内实验
控制细菌感染的诱导。氧甾醇生产、中间体和产物的动力学
待确定 2a) 构建氧化酶的组成和结构特性的分子库
hurpan 胆汁中胆固醇的产物'使用高效液相色谱 (HPLC),连接,,与 '''ij':^ j
质谱 (MS) 和 IMS/MS。 2$),表征“ithe”的物理化学和生物功能“这些;|y”,|
氧甾醇。 3) 使用氧甾醇与正常人胆管(胆囊)上皮细胞长期共培养至'''/1
诱发癌变。细胞形态/癌症jgrqwth途径将在V之前、du'ringian和之后确定
癌症形成。, _ __, 'jfv \t\ '¿, V'1' 'li'i !!'' JU'H . 。 '??!;! :!''<'.! i"V ¿ ,'i1. ¿.!
该提案采用多学科方法,包括结构生物化学、细胞和分子生物学,
和物理化学方法。它有望开辟胆道生理学和新陈代谢的新领域;
创建人类胆固醇氧化产物的分子库;增加新的、重要的理解和
深入了解胆管癌的病因;并指导这一重要且重要的疾病的战略治疗和预防
维辛克病。
项目成果
期刊论文数量(0)
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{{ truncateString('SUM P LEE', 18)}}的其他基金
The effect of physical activity on metabolic syndrome in pregnancy and fetal outc
体力活动对妊娠期代谢综合征及胎儿结局的影响
- 批准号:
7197667 - 财政年份:2007
- 资助金额:
$ 21.24万 - 项目类别:
Regulation of cell lineage specificity in the liver
肝脏细胞谱系特异性的调节
- 批准号:
6865625 - 财政年份:2003
- 资助金额:
$ 21.24万 - 项目类别:
Regulation of cell lineage specificity in the liver
肝脏细胞谱系特异性的调节
- 批准号:
6740157 - 财政年份:2003
- 资助金额:
$ 21.24万 - 项目类别:
Regulation of cell lineage specificity in the liver
肝脏细胞谱系特异性的调节
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6572883 - 财政年份:2003
- 资助金额:
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6138010 - 财政年份:1996
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