15-LOX-1 Regulation of Resolving Generation to Modulate Colon Cancer
15-LOX-1 调节分解生成以调节结肠癌
基本信息
- 批准号:9980183
- 负责人:
- 金额:$ 25.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:ALOX15 geneAffectApoptosisArachidonate 15-LipoxygenaseArachidonate 5-LipoxygenaseAttenuatedAzoxymethaneBreedingCancerousCell Differentiation processCell ProliferationCell RespirationCellsChemopreventionChemopreventive AgentClinicalColitisColon CarcinomaColorectal CancerCyclin D1DataDevelopmentDietDiffusionDown-RegulationEnzyme ImmunoassayEnzymesEpithelial CellsEventFDA approvedFish OilsFormulationFutureGenerationsGenesGeneticGenetic TranscriptionGoalsHealthHumanHyperlipidemiaIncidenceIntegration Host FactorsInterleukin-1 betaInterventionIntestinesKnock-outKnockout MiceLOX geneLengthLentivirus VectorLeukocytesLipoxygenase 1MeasuresMediatingMessenger RNAMetabolismMolecularMolecular TargetMusMutationOmega-3 Fatty AcidsOrganoidsPathway interactionsPatientsPharmacologic SubstancePhasePreventiveProductionProteinsQuantitative Reverse Transcriptase PCRRegulationResearchShapesSignal PathwaySignal TransductionSubfamily lentivirinaeTNF geneTestingTransgenic OrganismsWorkbasebeta cateninc-myc Genescancer chemopreventioncolon cancer preventioncolon tumorigenesiscolonic cryptdietary supplementsgain of functionimprovedintestinal epitheliumliquid chromatography mass spectrometryloss of functionmouse modelnovelpremalignantpreventreconstitutionsmall hairpin RNAtumortumorigenesis
项目摘要
Our long-term goal is to develop novel interventions to prevent colorectal tumorigenesis (CRT). The effects of
fish oil and its omega-3 fatty acid derivatives DHA and EPA on CRT are controversial: some studies show
promotion and others suppression. We found in preliminary studies that fish oil promoted while EPA inhibited
colitis-associated CRT. Whether these differences are applicable to sporadic CRT is unknown. This is clinically
important because DHA and EPA are widely used as dietary supplements and FDA-approved treatments. 15-
lipoxygenase-1 (15-LOX-1) is a critical enzyme for DHA and EPA oxidative metabolism to generate resolvins
and their precursors (e.g., 18-HEPE and RvEs, 17-HDHA and RvEs). 15-LOX-1 and resolvins suppress im-
portant pathways (e.g., TNF-α, IL-1β) that potentiate aberrant Wnt/beta-catenin (Wnt/B-catenin) signaling,
which is a driver of CRT. 15-LOX-1 expression is commonly lost early during human CRT. Whether 15-LOX-1
expression loss reduces resolvin production from DHA and EPA and reduces the effects of DHA and EPA on
CRT is unknown. Our preliminary data show that intestinally targeted 15-LOX-1 expression (15-LOX-1-Gut
mice) enhanced resolvin production, suppressed APC mutation-driven B-catenin activation and CRT, attenuat-
ed DHA-induced CRT promotion, and enhanced EPA-induced CRT suppression. We hypothesize that 15-LOX-
1 expression in colonic epithelial cells is critical for DHA and EPA to generate resolvins and modulate Wnt/B-
catenin signaling and CRT. Aims 1 and 2 will determine the effects of 15-LOX-1 gain (aim 1) and loss of func-
tion (aim 2) in colonic epithelial cells on resolvin generation from DHA and EPA, CRT, and B-catenin signaling.
For aim 1, we will use 15-LOX-1-Gut mice. For aim 2, we will breed mice with intestinal 12-S-LOX transgenic
expression with 12/15-LOX knockout mice to target 12-S-LOX reconstitution to intestinal epithelial cells. In both
aims, mice will be fed control, DHA, or EPA diet and treated with AOM to induce CRT. Groups will be com-
pared for resolvins and their precursors, CRT, cell proliferation and apoptosis, TNF-α, IL-1β, and activated B-
catenin levels, and Wnt/B-catenin target gene (c-Myc, Cyclin D1, Axin2) mRNA levels. We will also evaluate
the effect of 15-LOX-1 gain of function (aim 1) and downregulation (aim 2) in human colonic cancerous and
normal organoids isolated from patients' colonic crypts and cultured with various concentrations of EPA and
DHA on resolvin generation, cell proliferation, cell differentiation, and Wnt/B-catenin signaling. Aim 3 will de-
termine the temporal effects of 15-LOX-1 expression in colonic epithelial cells and in leukocytes on resolvin
generation and CRT. 15-LOX-1 transgenic expression will be targeted to intestinal epithelial cells and induced
at either initiation or progression phases of AOM-induced CRT (subaim 3A) or targeted to leukocytes prior to
AOM-induced CRT (subaim 3B). Mice will be fed DHA or EPA diets and compared for end points described for
aims 1 and 2. Our findings will direct efforts to develop interventions to prevent CRT based on understanding
of the host factors (e.g., 15-LOX-1) that affect DHA and EPA modulation of CRT.
我们的长期目标是开发新的干预措施来预防结直肠肿瘤发生(CRT)。的影响
鱼油及其omega-3脂肪酸衍生物DHA和EPA对CRT的影响是有争议的:一些研究表明,
促进和其他抑制。我们在初步研究中发现,鱼油促进,而EPA抑制
结肠炎相关CRT。这些差异是否适用于偶发CRT尚不清楚。这是临床上
重要的是,DHA和EPA被广泛用作膳食补充剂和FDA批准的治疗方法。15-
脂氧合酶-1(15-LOX-1)是DHA和EPA氧化代谢生成消退素的关键酶
和它们的前体(例如,18-HEPE和RvE、17-HDHA和RvE)。15-LOX-1和resolvins抑制IM-
重要途径(例如,TNF-α,IL-1β),其增强异常Wnt/β-连环蛋白(Wnt/β-连环蛋白)信号传导,
其是CRT的驱动器。15-LOX-1的表达通常在人CRT早期丢失。15-LOX-1是否
表达缺失减少了DHA和EPA的消退素产生,并降低了DHA和EPA对
CRT未知。我们的初步数据显示,在大肠杆菌中,15-LOX-1-Gut表达是一种靶向的15-LOX-1表达。
小鼠)增强消退素的产生,抑制APC突变驱动的B-连环蛋白激活和CRT,减弱
艾德抑制了DHA诱导的CRT促进,并增强了EPA诱导的CRT抑制。我们假设15-LOX-
1在结肠上皮细胞中的表达对于DHA和EPA产生消退素和调节Wnt/B-1是至关重要的。
连环蛋白信号传导和CRT。目的1和2将决定15-LOX-1增加(目的1)和功能丧失的影响。
在结肠上皮细胞中对来自DHA和EPA、CRT和B-连环蛋白信号传导的消退素产生的作用(目的2)。
对于目标1,我们将使用15-LOX-1-Gut小鼠。目的二是培育肠道12-S-LOX转基因小鼠
用12/15-LOX敲除小鼠表达12-S-LOX以将12-S-LOX重建靶向肠上皮细胞。无论是
为了达到目的,小鼠将被喂食对照、DHA或EPA饮食并用AOM处理以诱导CRT。团体将在-
对消退素及其前体、CRT、细胞增殖和凋亡、TNF-α、IL-1β和活化的B-
连环蛋白水平和Wnt/B-连环蛋白靶基因(c-Myc、Cyclin D1、Axin 2)mRNA水平。我们还将评估
15-LOX-1在人结肠癌中的功能获得(aim 1)和下调(aim 2)的作用,
从患者的结肠隐窝中分离并与各种浓度的EPA培养的正常类器官,
DHA对消退素生成、细胞增殖、细胞分化和Wnt/B-连环蛋白信号传导的影响。目标3将-
确定结肠上皮细胞和白细胞中15-LOX-1表达对消退的时间效应
一代和CRT。15-LOX-1转基因表达将靶向肠上皮细胞并诱导
在AOM诱导的CRT的起始或进展阶段(子目的3A)或在
AOM诱导的CRT(子目标3B)。小鼠将被喂食DHA或EPA饮食,并比较针对以下描述的终点:
目标1和2。我们的研究结果将指导努力开发干预措施,以防止CRT的基础上了解
宿主因素(例如,15-LOX-1)影响DHA和EPA对CRT的调节。
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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Imad Shureiqi其他文献
Imad Shureiqi的其他文献
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{{ truncateString('Imad Shureiqi', 18)}}的其他基金
ALOX15 regulation of colon cancer invasiveness via PI3P-linoleic acid metabolism
ALOX15 通过 PI3P-亚油酸代谢调节结肠癌侵袭力
- 批准号:
10339182 - 财政年份:2022
- 资助金额:
$ 25.06万 - 项目类别:
ALOX15 regulation of colon cancer invasiveness via PI3P-linoleic acid metabolism
ALOX15 通过 PI3P-亚油酸代谢调节结肠癌侵袭性
- 批准号:
10545078 - 财政年份:2022
- 资助金额:
$ 25.06万 - 项目类别:
15-LOX-1 Modulation of Colon Cancer Promotion by Linoleic Acid
亚油酸对 15-LOX-1 促进结肠癌的调节
- 批准号:
10330050 - 财政年份:2021
- 资助金额:
$ 25.06万 - 项目类别:
15-LOX-1 regulation of resolving generation to modulate colon cancer
15-LOX-1 调节分解生成以调节结肠癌
- 批准号:
10301423 - 财政年份:2016
- 资助金额:
$ 25.06万 - 项目类别:
15-LOX-1 Modulation of Colon Cancer Promotion by Linoleic Acid
亚油酸对 15-LOX-1 促进结肠癌的调节
- 批准号:
9886073 - 财政年份:2016
- 资助金额:
$ 25.06万 - 项目类别:
15-LOX-1 Regulation of Resolving Generation to Modulate Colon Cancer
15-LOX-1 调节分解生成以调节结肠癌
- 批准号:
9187612 - 财政年份:2016
- 资助金额:
$ 25.06万 - 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
- 批准号:
7987654 - 财政年份:2010
- 资助金额:
$ 25.06万 - 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
- 批准号:
8259197 - 财政年份:2010
- 资助金额:
$ 25.06万 - 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
- 批准号:
8091356 - 财政年份:2010
- 资助金额:
$ 25.06万 - 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
- 批准号:
8657861 - 财政年份:2010
- 资助金额:
$ 25.06万 - 项目类别:
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