Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions
Ah受体-MicroRNA相互作用的分子机制及应用
基本信息
- 批准号:8269955
- 负责人:
- 金额:$ 25.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:7-ketocholesterolAdverse effectsAffinityAgonistAromatic AminesAromatic CompoundsAromatic Polycyclic HydrocarbonsAryl Hydrocarbon ReceptorBenzo(a)pyreneBilirubinBindingBiochemicalBreast Cancer CellCYP1A1 geneCancer cell lineCell LineCell ProliferationCellsChemopreventive AgentChemoprotective AgentCleft PalateCytotoxic agentDevelopmentDioxinsDiseaseDisease-Free SurvivalElementsEndometrial CarcinomaEstrogen AntagonistsEstrogen Receptor ModulatorsEstrogen ReceptorsEstrogen receptor negativeEstrogensExhibitsFamilyFlavonoidsFoodGenesGrowthIndole-3-CarbinolInkLaboratoriesLigandsMalignant neoplasm of prostateMammary NeoplasmsMediatingMetabolismMicroRNAsMolecularMusNuclear ReceptorsNude MicePatientsPharmaceutical PreparationsPharmacologic SubstancePhytochemicalPorphyriasProtein BindingRegulationResearchRoleStagingTetrachlorodibenzodioxinTissuesToxic Environmental SubstancesXenograft procedurechemotherapyclinical applicationimmunotoxicityin vivomalignant breast neoplasmmembermigrationoutcome forecastpancreatic cancer cellsreceptorreceptor bindingresponsetranscription factortumor growth
项目摘要
PROJECT SUMMARY
The aryl hydrocarbon receptor (AhR) was initially discovered as an intracellular protein that binds to the
environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related chlorinated
aromatic compounds. In recent years, it has been demonstrated that the AhR binds with structurally and
functionally diverse compounds including chemoprotective phytochemicals such as flavonoids, polyphenolics
and indole-3-carbinol. Not surprisingly, these compounds exhibit tissue-specific AhR agonist and antagonist
activities and can be classified as selective AhR modulators (SAhRMs). Previous studies in this laboratory
have taken advantage of the potential applications of SAhRMs for treatment of diseases, and 6-methyl-1,3,8-
trichlorodibenzofuran (MCDF) was initially characterized as an AhR antagonist but, like TCDD, MCDF
exhibited antiestrogenic activity in estrogen-responsive breast cancer cells and mammary tumors, and MCDF
is a potent antiestrogen that acts through inhibitory AhR-estrogen receptor (ER) crosstalk. Results of
preliminary studies now show that AhR agonists such as TCDD and MCDF inhibit growth of a large number of
ER-negative breast cancer cells including highly invasive MDA-MB-231 and MDA-MB-468 cells that are
classified as basal or triple negative cells. MCDF also inhibits tumor growth in vivo in athymic nude mice
bearing ER-negative cells as xenografts. Moreover, the antitumorigenic activity of MCDF and TCDD is
accompanied by AhR-dependent induction of two antimetastatic microRNAs (miRs), namely miR-335 and miR-
205. The proposed studies will further investigate the molecular mechanisms and potential clinical applications
of MCDF and structurally-related SAhRMs for treatment of ER-negative breast cancer. Aim 1 will focus on
SAhRM-induced modulation of miR-335 and miR-205 and the role of the AhR in decreasing the proliferation,
migration and invasion of a panel of ER-negative breast cancer cell lines. In Aim 2, the mechanism of AhR-
dependent regulation of miR-335 and miR-205 expression will be determined ER-negative breast cancer cell
lines and the functional dioxin responsive elements (DREs) regulating miR expression will be identified. In
addition, genes regulated by AhR-miR-335 and AhR-miR-205 interactions will also be investigated. Aim 3 will
confirm the role of the AhR, miR-335 and miR-205 in regulating orthotopic mammary tumor growth in athymic
nude mice using cell lines in which expression of the AhR, miR-335 and miR-205 is regulated. The proposed
studies will be the first to characterize the molecular mechanisms of AhR-miR interactions and development of
SAhRMs for clinical applications in the treatment of ER-negative breast cancer.
项目总结
芳香烃受体(AhR)最初是作为一种细胞内蛋白被发现的,它与
环境毒物2,3,7,8-四氯二苯并对二恶英(TCDD)及其结构相关性氯化
芳香化合物。近年来,已有研究表明,AhR在结构上与
功能多样的化合物,包括化学保护植物化学物质,如黄酮类、多酚类
和吲哚-3-甲醇。毫不奇怪,这些化合物显示出组织特异性的AhR激动剂和拮抗剂。
活性,并可被归类为选择性AhR调节器(SAhRM)。本实验室以前的研究
已利用SAhRms在治疗疾病方面的潜在应用,以及6-甲基-1,3,8-
三氯二苯并呋喃(MCDF)最初的特征是AhR拮抗剂,但与TCDD一样,MCDF
在雌激素反应的乳腺癌细胞和乳腺肿瘤中显示出抗雌激素活性,MCDF
是一种有效的抗雌激素,通过抑制AhR-雌激素受体(ER)串扰发挥作用。结果:
初步研究表明,AhR激动剂,如TCDD和MCDF,可抑制大量
ER阴性的乳腺癌细胞包括高侵袭性的MDA-MB-231和MDA-MB-468细胞
分类为基底性或三重负性细胞。MCDF还能抑制裸鼠体内肿瘤生长
携带ER阴性细胞作为异种移植。此外,MCDF和TCDD的抗肿瘤活性是
伴随着对两个抗转移microRNAs(MiR)的依赖于AhR的诱导,即miR-335和miR-
205.拟议的研究将进一步探讨分子机制和潜在的临床应用。
MCDF和结构相关SAhRMs用于治疗ER阴性乳腺癌。目标1将专注于
SAHRM诱导miR-335和miR-205的调控以及AhR在抑制增殖中的作用
一组ER阴性乳腺癌细胞系的迁移和侵袭。在目标2中,AhR-
将确定ER阴性乳腺癌细胞对miR-335和miR-205表达的依赖性调节
将识别调控miR表达的二恶英反应元件(DREs)。在……里面
此外,还将研究由AhR-miR-335和AhR-miR-205相互作用调节的基因。目标3将
确认AhR、miR-335和miR-205在裸鼠原位乳腺肿瘤生长调控中的作用
裸鼠使用AhR、miR-335和miR-205表达受调控的细胞系。建议数
研究将首次表征AhR-miR相互作用的分子机制和
SAhRms在ER阴性乳腺癌治疗中的临床应用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Stephen H. Safe其他文献
Stephen H. Safe的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Stephen H. Safe', 18)}}的其他基金
Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions
Ah受体-MicroRNA相互作用的分子机制及应用
- 批准号:
8098965 - 财政年份:2010
- 资助金额:
$ 25.92万 - 项目类别:
Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions
Ah受体-MicroRNA相互作用的分子机制及应用
- 批准号:
7984095 - 财政年份:2010
- 资助金额:
$ 25.92万 - 项目类别:
Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions
Ah 受体-MicroRNA 相互作用的分子机制及应用
- 批准号:
8676462 - 财政年份:2010
- 资助金额:
$ 25.92万 - 项目类别:
Molecular Mechanisms and Application of Ah Receptor-MicroRNA Interactions
Ah受体-MicroRNA相互作用的分子机制及应用
- 批准号:
8470085 - 财政年份:2010
- 资助金额:
$ 25.92万 - 项目类别:
MicroRNAs as Targets for Colon Cancer Chemotherapy
MicroRNA 作为结肠癌化疗的靶点
- 批准号:
8064803 - 财政年份:2009
- 资助金额:
$ 25.92万 - 项目类别:
MicroRNAs as Targets for Colon Cancer Chemotherapy
MicroRNA 作为结肠癌化疗的靶点
- 批准号:
8260227 - 财政年份:2009
- 资助金额:
$ 25.92万 - 项目类别:
MicroRNAs as Targets for Colon Cancer Chemotherapy
MicroRNA 作为结肠癌化疗的靶点
- 批准号:
7563104 - 财政年份:2009
- 资助金额:
$ 25.92万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 25.92万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 25.92万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 25.92万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 25.92万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 25.92万 - 项目类别:
Studentship