Exploring the role of progestin and vitamin D on inflammation and oxidative stress in in vitro and in vivo models of ovarian cancer
探索孕激素和维生素 D 对卵巢癌体外和体内模型炎症和氧化应激的作用
基本信息
- 批准号:10064375
- 负责人:
- 金额:$ 6.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:Abdominal CavityAffectBenignBiologicalBiological AssayC-reactive proteinCD3 AntigensCD44 geneCalcitriolCarcinoma in SituCell LineCell NucleusCellsDNADNA DamageDevelopmentDisease modelDominant-Negative MutationEnzyme-Linked Immunosorbent AssayEpithelialEpitheliumEventExposure toFemaleFormulationGenesGynecologic Surgical ProceduresH2AFX geneHydrogen PeroxideIL8 geneITGAM geneImmunofluorescence ImmunologicImmunohistochemistryIn VitroIncidenceInflammationInflammation MediatorsInflammatoryInterleukin-6Knockout MiceLeadLesionLevonorgestrelMS4A1 geneMalignant NeoplasmsMalignant neoplasm of ovaryMammalian OviductsMediator of activation proteinMedroxyprogesterone 17-AcetateModelingMolecularMolecular AnalysisMolecular GeneticsMusMutationNorethindroneOvarianOvaryOxidative StressOxidative Stress PathwayPTEN genePTPRC geneParaffinPharmacologyPlasmaPostmenopausePreventionPrevention trialPreventivePrimary Cell CulturesProgesteroneProgestinsProtein p53ProteinsRNAReactive Oxygen SpeciesReproducibilityRoleS-Phase FractionSamplingSecretory CellSerousStainsSurfaceTNF geneTP53 geneTechniquesTestingTimeTubeUrokinase Plasminogen Activator ReceptorVitamin DWestern BlottingWomanWorkanalogcarcinogenesisexperimental studyfimbriain vivo Modelmonocytemortalitymouse modelmutantovarian cancer preventionp53-binding protein 1parent grantresponse
项目摘要
Project Summary/Abstract
In the early stages of ovarian carcinogenesis, it is now thought that the fimbria acquires molecular
and genetic alterations when exposed to inflammatory mediators and associated oxidative stress
(reactive oxygen species-ROS) released during ovulatory events from the adjacent ovary. These
changes lead to the “p53 signature”- accumulation of mutant p53 protein (earliest genetic
alteration in ovarian cancer), in the secretory cells of the fimbria ultimately leading to the
development of serous tubal intraepithelial carcinoma (STIC), which spreads via
shedding/exfoliation directly to the adjacent ovary and into the abdominal cavity. The p53
signatures and STIC lesions which evolve in an inflammatory, oxidative and DNA-toxic
microenvironment are characterized by distinct features including loss of polarity, epithelial tufting,
pleomorphic nuclei, abnormal p53 expression and a high-proliferative index. The discovery of
these lesions and how they develop opens the door to the formulation of pharmacologic strategies
that arrest and/or reverse the early transformative events in the fimbria, with immense potential
to decrease ovarian cancer incidence and mortality through prevention.
Previously, our work has focused primarily on the ovarian surface epithelium as the biologic target
for ovarian cancer prevention using progestins and vitamin D. However, little is known regarding
their biologic effects in the FTE. The objective of this study is to explore the impact of
progestin and vitamin D on inflammation and oxidative stress in early carcinogenesis of
ovarian cancer in in vitro and in vivo models of the disease. We hypothesize that inhibition
of inflammatory and oxidative effects may comprise a biologic mechanism contributing to the
cancer preventive effects of these agents. Furthermore, we will examine whether the combination
of progestin and vitamin D is more effective than either agent alone. To test this hypothesis, we
will utilize the following samples from the parent grant to evaluate inflammatory and oxidative
stress pathways following administration of progestin and vitamin D: (1) cell cultures of primary
FTE as well as transformed FTE harboring dominant negative mutant p53 obtained and
established from pre- and postmenopausal women undergoing gynecologic surgery for benign
indications, (2) paraffin sections of the fallopian tube and corresponding isolates (RNA, DNA,
protein and plasma/serum) obtained from the mice (mogp-TAg and Dicer-PTEN) undergoing
prevention trials with progestins and vitamin D.
项目摘要/摘要
在卵巢癌发生的早期阶段,现在认为菌毛获得了分子
以及暴露于炎症介质和相关氧化应激时的遗传变化
(活性氧种-ROS)在排卵过程中从相邻卵巢释放。这些
变化导致“P53特征”--突变型P53蛋白积聚(最早的基因
卵巢癌的改变),在海马伞的分泌细胞中最终导致
浆液性输卵管上皮内癌(STIC)的发生发展
脱落/剥落直接进入邻近的卵巢并进入腹膜。P53
在炎症、氧化和DNA中毒的过程中演变的特征和STIC损害
微环境具有明显的特征,包括极性丧失,上皮丛生,
细胞核多形性、P53异常表达和高增殖指数。发现了
这些损伤和它们如何发展打开了制定药理学策略的大门
这阻止和/或扭转了海流带早期的变革性事件,具有巨大的潜力
通过预防降低卵巢癌的发病率和死亡率。
以前,我们的工作主要集中在卵巢表面上皮细胞作为生物学靶点。
使用孕激素和维生素D预防卵巢癌,然而,关于
它们在FTE中的生物效应。这项研究的目的是探讨
孕激素和维生素D对卵巢癌早期致癌中炎症和氧化应激的影响
卵巢癌在体外和体内的疾病模型。我们假设抑制作用
炎症和氧化作用可能包括一种生物机制,有助于
这些制剂对癌症的预防作用。此外,我们将研究这一组合是否
黄体酮和维生素D的结合比任何一种单独使用都更有效。为了检验这一假设,我们
将利用来自父母资助的以下样本来评估炎症和氧化
孕激素和维生素D应激途径:(1)原代细胞培养
FTE以及含有显性负突变体P53的转化FTE,并
由绝经前和绝经后接受良性妇科手术的妇女建立
适应症,(2)输卵管石蜡切片和相应的分离株(RNA,DNA,
从小鼠(mogp-tag和Dird-PTEN)中获得的蛋白质和血浆/血清)
孕激素和维生素D的预防试验
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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Gustavo Rodriguez其他文献
Gustavo Rodriguez的其他文献
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{{ truncateString('Gustavo Rodriguez', 18)}}的其他基金
Vitamin D and Progestins for the Chemoprevention of Fallopian Tube/Ovarian Cancer
维生素 D 和孕激素用于输卵管/卵巢癌的化学预防
- 批准号:
10302294 - 财政年份:2017
- 资助金额:
$ 6.51万 - 项目类别:
Vitamin D and Progestins for the Chemoprevention of Fallopian Tube/Ovarian Cancer
维生素 D 和孕激素用于输卵管/卵巢癌的化学预防
- 批准号:
10053715 - 财政年份:2017
- 资助金额:
$ 6.51万 - 项目类别:
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