Role of GPR30 in Hepatic Lipid Metabolism
GPR30 在肝脏脂质代谢中的作用
基本信息
- 批准号:8917341
- 负责人:
- 金额:$ 18.94万
- 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:2014-09-15 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAgeBasic ScienceBile Acid Biosynthesis PathwayBile AcidsBile fluidBiliaryCYP7A1 geneCell NucleusChemicalsCholelithiasisCholesterolCholesterol HomeostasisChromosomes, Human, Pair 5Clinical ResearchConjugated EstrogensCrystallizationDataDevelopmentDietEndoplasmic ReticulumEpidemicEpidemiologic StudiesEpidermal Growth Factor ReceptorEquilibriumEstrogen ReceptorsEstrogen TherapyEstrogensFeedbackFemaleG-Protein-Coupled ReceptorsGallbladderGenderGenesHepaticHepatocyteHumanKnowledgeLiverLiver FailureMalignant neoplasm of prostateMapsMediatingMembraneMetabolicMissionMolecularMolecular GeneticsMucinsMusOral ContraceptivesOutcomeOutputPathway interactionsPatientsPlayPopulationPre-Clinical ModelPrecipitationPredispositionPrevalencePreventionPreventive InterventionPublishingReceptor SignalingRegulationResearchRiskRisk FactorsRoleSRE-2 binding proteinSignal PathwaySignal TransductionSolidSolubilitySteroidsTestingTherapeutic InterventionTimeTranslatingUnited StatesUnited States National Institutes of HealthWomanWorkabsorptionbasecell motilityfeedinginnovationlipid metabolismliquid crystalmenmodel designnovelnovel strategiespreventrapid growthresponse
项目摘要
Epidemiological and clinical studies have found that cholesterol gallstones are more prevalent in women than
in men at all ages in every population that has been studied. Accumulated evidence clearly shows that the use
of oral contraceptive steroids and conjugated estrogens in women significantly increases the prevalence of
cholesterol gallstones. Estrogen therapy to men with prostatic cancer also leads to similar lithogenic effects.
These findings show that the increased risk of gallstones in women compared to men is related to differences
in how the liver metabolizes cholesterol in response to estrogen. Our published studies have established a
central role for estrogen by activating hepatic estrogen receptor α (ERα), but not ERβ, in promoting gallstone
formation. However, the mechanisms mediating estrogen’s lithogenic actions on gallstone formation have
become more complicated with the identification of a novel estrogen receptor, the G protein-coupled receptor
30 (GPR30). Furthermore, Gpr30 has been mapped to mouse chromosome 5 and is co-localized with Lith18, a
new gallstone gene. Our molecular and genetic data support the candidacy of the Gpr30 gene as a compelling
gene underlying Lith18. However, identifying the lithogenic mechanism of GPR30 remains a significant
challenge because it is not yet fully understood whether GPR30 plays a major role in estrogen-induced
gallstones and whether it acts independently of or in conjunction with ERα on inducing cholesterol gallstones.
Our central hypothesis is that GPR30 is also involved in estrogen-dependent lithogenic actions, working
independently of ERα, as both GPR30 and ERα can work through different pathways to promote the formation
of estrogen-induced gallstones. The rationale for the proposed research is that once the particular mechanisms
as to how estrogen increases susceptibility to gallstone formation through GPR30 are understood, the key
components of estrogen signaling could be manipulated pharmacologically, leading to innovative targets to the
treatment of gallstones in women. Guided by our preliminary data, we propose to test this hypothesis by
pursuing three specific aims: first, to investigate the phenotypic characterization of GPR30 that determines
susceptibility to cholesterol cholelithiasis; second, to study whether GPR30 activation of EGFR leads to the
lithogenesis of bile by inhibiting hepatic bile acid synthesis in response to high levels of estrogen; and third, to
elucidate the critical role of GPR30 in hepatic hypersecretion of biliary cholesterol and gallbladder hypomotility
that accounts for rapid growth of cholesterol crystals. This application is innovative because distinguishing the
lithogenic actions of GPR30 from those of ERα and further investigating how estrogen produces lithogenic
actions through GPR30 will help elucidate all the molecular mechanisms behind the formation of estrogeninduced
cholesterol gallstones. The proposed research is significant because it translates basic research
discovery to a pre-clinical model designed to identify novel treatment targets and may provide an efficacious
novel strategy for the prevention of gallstones in women and in patients exposed to high levels of estrogen.
流行病学和临床研究发现,胆固醇结石在女性中比
在所有被研究的人群中,所有年龄段的男性中。积累的证据清楚地表明,使用
口服避孕药类固醇和结合雌激素在妇女中的使用显著增加了
胆固醇结石。前列腺癌患者接受雌激素治疗也会产生类似的致石作用。
这些发现表明,与男性相比,女性患胆结石的风险增加与差异有关。
肝脏如何代谢胆固醇对雌激素的反应。我们发表的研究已经建立了一个
雌激素通过激活肝脏雌激素受体α(ERα)而不是ERβ在促进胆结石中的中枢作用
队形。然而,调节雌激素对胆结石形成的致石作用的机制有
随着一种新的雌激素受体--G蛋白偶联受体的鉴定变得更加复杂
30(GPR30)。此外,Gpr30已经被定位到小鼠的5号染色体上,并与Lith18,a
新的胆结石基因。我们的分子和遗传数据支持Gpr30基因作为一种引人注目的候选基因
18号结石背后的基因。然而,确定GPR30的致石机制仍然具有重要意义
挑战,因为目前还不完全清楚GPR30是否在雌激素诱导中起主要作用
以及它是否独立于ERα或与ER DNA共同作用于诱导胆固醇结石。
我们的中心假设是,GPR30也参与了雌激素依赖性的致石作用,
独立于ERα,因为GPR30和ERα都可以通过不同的途径促进形成
雌激素引起的胆结石。提出这项研究的理由是,一旦特定的机制
至于雌激素如何通过GPR30增加胆结石形成的易感性已被了解,关键是
雌激素信号的成分可以被药理学操纵,导致创新的靶点
女性胆结石的治疗。在我们初步数据的指导下,我们建议通过以下方式来检验这一假设
追求三个具体目标:第一,研究决定GPR30的表型特征
第二,研究GPR30激活EGFR是否导致
通过抑制肝脏胆汁酸的合成来应对高水平的雌激素而导致的胆汁结石形成;第三,
GPR30在肝脏胆汁胆固醇高分泌和胆汁动力低下中的关键作用
这就是胆固醇晶体快速生长的原因。此应用程序具有创新性,因为区分
GPR30与ER-α的致石作用及雌激素致石机制的进一步研究
通过GPR30的作用将有助于阐明雌激素诱导的雌激素形成的所有分子机制
胆固醇结石。拟议的研究具有重要意义,因为它翻译了基础研究
发现一种临床前模型,旨在识别新的治疗靶点,并可能提供有效的
预防女性和暴露于高水平雌激素患者的胆结石的新策略。
项目成果
期刊论文数量(0)
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DAVID Q WANG其他文献
DAVID Q WANG的其他文献
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{{ truncateString('DAVID Q WANG', 18)}}的其他基金
The Role of Dysfunctional CCK-1R in Cholelithogenesis
功能失调的 CCK-1R 在胆石形成中的作用
- 批准号:
7369647 - 财政年份:2008
- 资助金额:
$ 18.94万 - 项目类别:
The Role of Dysfunctional CCK-1R in Cholelithogenesis
功能失调的 CCK-1R 在胆石形成中的作用
- 批准号:
8018566 - 财政年份:2008
- 资助金额:
$ 18.94万 - 项目类别:
The Role of Dysfunctional CCK-1R in Cholelithogenesis
功能失调的 CCK-1R 在胆石形成中的作用
- 批准号:
7556320 - 财政年份:2008
- 资助金额:
$ 18.94万 - 项目类别:
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