Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus
Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus
批准号:
8434197
负责人:
RHONDA F SOUZA
金额:
$23.84万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-04-01 至 2015-01-31
关键词:
AcidsAdenocarcinomaAdenocarcinoma CellAdultAffectAmericanApoptosisApoptoticBarrett EsophagusBenignBile AcidsBile RefluxCell LineCell ProliferationCell SurvivalCellsChemopreventive AgentClinicalClinical DataClinical ResearchDNA DamageDataDeoxycholic AcidDevelopmentDiseaseEpithelialEpithelial CellsEsophagealEsophageal AdenocarcinomaEsophageal NeoplasmsEsophageal Squamous CellEsophagusEventExposure toFrequenciesGastric JuiceGastroesophageal reflux diseaseGrowthHomeostasisHumanHydrochloric AcidIn VitroIncidenceInterventionIntestinesLaboratoriesLiteratureMalignant NeoplasmsMediatingMetaplasiaMetaplasticMetaplastic CellMetaplastic Columnar CellMetaplastic Epithelial CellModelingMolecularMutationNeoplasmsPathogenesisPathway interactionsPatientsPlayPredispositionPrevention strategyProcessProliferatingProteinsProton Pump InhibitorsPublic HealthPublishingRefluxResistanceRisk FactorsRoleSignal PathwaySignal Transduction PathwaySpecimenSquamous CellSquamous EpitheliumSubgroupTechnologyTelomeraseTissuesUrsodeoxycholic Acidabstractingcancer preventioncarcinogenesisin vivoirradiationmolecular markerneoplasticpreventprotein expressionrepairedresponsetumortumor growthtumor progression
中文摘要
项目概要/摘要
胃食管反流病(GERD)和巴雷特食管(BE),这是非常常见的
在成年美国人中,这些疾病是食管腺癌的强危险因素。BE的频率-
在过去的几十年里,相关腺癌的发病率增加了六倍多,
对这种致命肿瘤的化学预防治疗受到对分子生物学的有限理解的阻碍。
BE发病机制和肿瘤进展的潜在事件。我们有初步数据显示,
Barrett上皮细胞对脱氧胆酸(DCA)(一种疏水性胆汁)诱导的凋亡更有抵抗力
反流的胃液中发现的酸,比通常衬在食管上的鳞状细胞要多。这种凋亡
耐药可能是Barrett化生的发病机制和持续性的基础,
死于胆汁酸诱导的凋亡的细胞被抗凋亡的巴雷特细胞所取代。
像DCA这样的疏水性胆汁酸也被证明会导致DNA损伤,
通常会引发细胞凋亡然而,我们有体外和体内研究的初步数据表明,
巴雷特细胞通过激活抗凋亡存活途径对胆汁酸诱导的DNA损伤作出反应。这
可以通过允许具有以下特征的细胞存活来促进巴雷特化生的肿瘤进展:
持续的致癌突变此外,我们的初步研究表明,食管鳞状细胞癌,
BE患者的细胞可能比食管癌患者的细胞更容易受到DNA损伤诱导的凋亡,
无BE的GERD患者的鳞状细胞。食管鳞状细胞的这种倾向,
细胞凋亡也可能促进BE的发展。我们的初步数据表明,NF-
B通路在Barrett化生的抗凋亡中起关键作用。我们也有初步数据
表明熊去氧胆酸(UDCA),一种亲水性胆汁酸,不会诱导遗传毒性损伤,
Barrett细胞在体外或体内,甚至保护免受DCA暴露引起的DNA损伤。这些
研究结果表明UDCA具有潜在的化学预防作用。最近,我们利用端粒酶技术
以产生永生但良性(非转化)的巴雷特细胞系和食管鳞状细胞系
有无BE的GERD患者。我们建议使用这些细胞系以及组织标本,
探索胆汁酸反流激活的调节细胞凋亡的分子通路,以及这些分子通路的作用。
BE的发展和肿瘤进展的途径。我们假设胆汁酸影响
通过影响NF-B通路导致食管细胞凋亡。本研究的目的是描述
胆汁酸对正常食管癌细胞DNA损伤、NF-B通路和细胞凋亡的影响
体外和体内患者的鳞状和化生Barrett细胞,以破坏关键的NF-B蛋白,
确定这些破坏对体外胆汁酸介导的细胞凋亡的影响,并确定是否
UDCA可以在体外保护毒性更强的胆汁酸对DNA损伤和凋亡的影响。
英文摘要
Project Summary/Abstract
Gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE), which are exceptionally common
disorders in adult Americans, are strong risk factors for esophageal adenocarcinoma. The frequency of BE-
associated adenocarcinoma has increased more than six-fold in the past few decades, and the development of
chemopreventive therapies for this lethal tumor has been hampered by limited understanding of the molecular
events underlying the pathogenesis and neoplastic progression of BE. We have preliminary data showing that
Barrett's epithelial cells are more resistant to apoptosis induced by deoxycholic acid (DCA), a hydrophobic bile
acid found in refluxed gastric juice, than the squamous cells that normally line the esophagus. Such apoptotic
resistance might underlie the pathogenesis and persistence of Barrett's metaplasia, as esophageal squamous
cells that succumb to bile acid-induced apoptosis are replaced by apoptosis-resistant Barrett's cells.
Hydrophobic bile acids like DCA also have been shown to cause DNA damage, and extensive DNA damage
normally triggers apoptosis. However, we have preliminary data from in vitro and in vivo studies showing that
Barrett's cells respond to bile acid-induced DNA damage by activating anti-apoptotic survival pathways. This
could facilitate the neoplastic progression of Barrett's metaplasia by allowing the survival of cells that have
sustained cancer-promoting mutations. Moreover, our preliminary studies suggest that esophageal squamous
cells from patients with BE may be more susceptible to apoptosis induced by DNA damage than esophageal
squamous cells from GERD patients without BE. This predisposition of esophageal squamous cells to
succumb to apoptosis also may contribute to the development of BE. Our preliminary data suggest that the NF-
¿B pathway plays a key role in the apoptotic resistance of Barrett's metaplasia. We also have preliminary data
showing that ursodeoxycholic acid (UDCA), a hydrophilic bile acid, does not induce genotoxic damage in
Barrett's cells in vitro or in vivo, and even protects against the DNA damage caused by DCA exposure. These
findings suggest a potential chemopreventive role for UDCA. Recently, we have used telomerase technology
to generate immortal, but benign (non-transformed), Barrett's cell lines and esophageal squamous cell lines
from GERD patients with and without BE. We propose to use these cell lines as well as tissue specimens to
explore the molecular pathways activated by bile-acid reflux that regulate apoptosis, and the role of those
pathways in the development and neoplastic progression of BE. We hypothesize that bile acids influence
apoptosis in esophageal cells through effects on the NF-¿B pathway. The aims of this study are to delineate
the effects of bile acids on DNA damage, on the NF-¿B pathway, and on apoptosis in normal esophageal
squamous and metaplastic Barrett's cells in vitro and in patients in vivo, to disrupt the key NF-¿B proteins and
determine the effects of those disruptions on bile-acid mediated apoptosis in vitro, and to determine whether
UDCA can protect against the effects of the more toxic bile acids on DNA injury and apoptosis in vitro.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1007/s10620-010-1165-x
发表时间:
2010-06
期刊:
DIGESTIVE DISEASES AND SCIENCES
影响因子:
3.1
作者:
[Jacobs, John William, Jr., Spechler, Stuart Jon]
通讯作者:
Spechler, Stuart Jon
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批准号:10532359
-
项目类别:
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资助金额:$36.1万
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财政年份:2020
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Reflux-Induced Epithelial-Mesenchymal Transition in Benign Barrett's Esophagus
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Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
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负责人:RHONDA F SOUZA
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依托单位:
Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
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批准号:8445155
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项目类别:
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资助金额:$0.0万
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Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
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Role of IL-6/STAT3 Signaling in the Neoplastic Progression of Barrett's Esophagus
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依托单位:
Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus
-
批准号:7684883
-
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资助金额:$26.15万
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财政年份:2009
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负责人:RHONDA F SOUZA
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依托单位:
Clinical Studies on Bile Acids in Barrett's Esophagus
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项目类别:
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Basic and Clinical Studies on the Role of Bile Acids in Barrett's Esophagus
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Role of Acid in the Development of Barrett's Esophagus
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依托单位:
国内基金
海外基金
大肠癌发生机制的adenoma-adenocarcinoma pathway同serrated pathway的关系的研究
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批准号:30840003
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项目类别:专项基金项目
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资助金额:12.0万元
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批准年份:2008
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负责人:焦宇飞
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依托单位: