Molecular targeting of PPAR-delta in colon cancer

结肠癌中 PPAR-δ 的分子靶向

基本信息

  • 批准号:
    7987654
  • 负责人:
  • 金额:
    $ 32.79万
  • 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 2015-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to help develop new molecularly targeted colon cancer treatments. Angiogenesis is critical for colonic tumorigenesis. The peroxisome proliferator-activated receptor-delta (PPAR-d) is upregulated in human colon cancer. Published data are discordant on the effects of germ line PPAR-d genetic knock out (KO) on intestinal tumorigenesis in APCMin mice and the effects of PPAR-d agonist on vascular endothelial growth factor (VEGF) expression in cancer cell lines and intestinal adenomas of APCMin mice. The impact of PPAR-d upregulation in cancer cells on angiogenesis and tumorigenesis remains to be determined. Our preliminary data show that targeted intestinal PPAR-d KO profoundly inhibited azoxymethane-induced murine colonic tumorigenesis and VEGF expression; PPAR-d re-expression in PPAR-d null HCT-116 (PPAR-d-KO) cells restored their ability to form liver metastases and enhanced VEGF and interleukin-8 (IL-8) expression; and liposomal PPAR-d siRNA inhibited tumorigenesis and PPAR-d, VEGF, and IL-8 expression in HCT-116 in mice. We hypothesize that PPAR-d overexpression in colon cancer cells upregulates VEGF and IL-8 expression to promote tumor angiogenesis and tumorigenesis. Aim 1 is to determine if PPAR-d specific expression in colon cancer cells promotes tumorigenesis and angiogenesis and upregulates VEGF and IL-8 expression, by examining the effects of PPAR-d re-expression in PPAR-d-KO cells on angiogenesis markers (e.g. CD31 immunohistochemistry; FITC-lectin assay), tumorigenesis (liver and lung metastasis formation), and VEGF and IL-8 expression (mRNA by quantitative RT-PCR, protein by ELISA) in nude mice. Aim 2 is to determine whether PPAR-d knockdown via systemic delivery of liposomal PPAR-d siRNA to colon cancer cells in vivo is sufficient to inhibit tumorigenesis and angiogenesis and downregulate VEGF and IL-8 expression, by examining the effects of liposomal PPAR-d siRNA on angiogenesis, tumorigenesis (liver and lung metastasis formation by HCT-116 and HT-29 cells in nude mice), and PPAR-d, VEGF, and IL-8 expression. Aim 3 is to determine VEGF role in PPAR-d promotion of angiogenesis and tumorigenesis, by examining in nude mice the effects of VEGF overexpression in PPAR-d-KO cells on angiogenesis and tumorigenesis; assessing the effects of VEGF liposomal-siRNA knockdown on angiogenesis and tumorigenesis promoted by PPAR-d re-expression in PPAR-d-KO cells; and comparing the effects of PPAR-d and VEGF downregulation (via liposomal siRNA) on angiogenesis and liver and lung metastasis formation by HCT-116 and HT-29 cells. Aim 4 is to determine IL-8 role in PPAR-d promotion of angiogenesis and tumorigenesis, as done for VEGF in specific Aim 3. In Aims 3 and 4, we will also investigate if PPAR-d binds to the VEGF and IL-8 promoters to enhance their transcription, using VEGF and IL-8 promoter-luciferase deletion construct assays, EMSA, and ChIP/real-time PCR in HCT- 116 cells with wild-type PPAR-d expression, PPAR-d overexpression, or PPAR-d-KO. Confirmation of the tested hypothesis could lead to developing PPAR-d-targeted therapy to inhibit tumorigenesis. PUBLIC HEALTH RELEVANCE: Increased production of the protein peroxisome proliferator-activated receptor delta (PPAR-d) is associated with colon cancer development; however, the molecular mechanisms involved need to be clarified. The proposed project aims to improve understanding of the molecular mechanisms by which PPAR-d contributes to aspects of colon cancer development, especially the ability of tumors to make new blood vessels. This improved understanding is expected to help determine whether PPAR-d would be a suitable molecular target for development of new drugs to treat colon cancer.
描述(由申请人提供):我们的长期目标是帮助开发新的分子靶向结肠癌治疗方法。血管生成是结肠肿瘤发生的关键。过氧化物酶体增殖物激活受体-δ(PPAR-d)在人结肠癌中上调。关于生殖系PPAR-d基因敲除(KO)对APCMin小鼠肠肿瘤发生的影响以及PPAR-d激动剂对APCMin小鼠癌细胞系和肠腺瘤中血管内皮生长因子(VEGF)表达的影响,已发表的数据不一致。癌细胞中PPAR-d上调对血管生成和肿瘤发生的影响仍有待确定。我们的初步数据显示,靶向肠PPAR-d KO显著抑制氧化偶氮甲烷诱导的小鼠结肠肿瘤发生和VEGF表达; PPAR-d无效HCT-116中PPAR-d的再表达(PPAR-d-KO)细胞恢复其形成肝转移的能力,并增强VEGF和白细胞介素-8(IL-8)表达;脂质体PPAR-d siRNA可抑制HCT-116小鼠肿瘤的发生及PPAR-d、VEGF和IL-8的表达。我们推测,PPAR-d在结肠癌细胞中的过表达上调VEGF和IL-8的表达,以促进肿瘤血管生成和肿瘤发生。目的1是通过检测PPAR-d-KO细胞中PPAR-d再表达对血管生成标志物的影响,确定结肠癌细胞中PPAR-d特异性表达是否促进肿瘤发生和血管生成,并上调VEGF和IL-8的表达(例如,CD 31免疫组织化学; FITC-凝集素测定),肿瘤发生(肝和肺转移形成)和VEGF和IL-8表达(mRNA通过定量RT-PCR,蛋白通过ELISA)。目的2是通过检查脂质体PPAR-d siRNA对血管生成、肿瘤发生、肿瘤转移和肿瘤转移的影响,确定通过脂质体PPAR-d siRNA全身递送至结肠癌细胞体内的PPAR-d敲低是否足以抑制肿瘤发生和血管生成并下调VEGF和IL-8表达。(HCT-116和HT-29细胞在裸鼠中的肝和肺转移形成)和PPAR-d、VEGF和IL-8表达。目的3通过在裸鼠中检测VEGF在PPAR-d-KO细胞中过表达对血管生成和肿瘤发生的影响,评估VEGF脂质体-siRNA敲低对PPAR-d-KO细胞中PPAR-d再表达促进的血管生成和肿瘤发生的影响,确定VEGF在PPAR-d促进血管生成和肿瘤发生中的作用。比较PPAR-d和VEGF下调(通过脂质体siRNA)对HCT-116和HT-29细胞的血管生成以及肝和肺转移形成的影响。目的4是确定IL-8在PPAR-d促进血管生成和肿瘤发生中的作用,如在特定目的3中对VEGF所做的那样。在目标3和4中,我们还将在野生型PPAR-d表达、PPAR-d过表达或PPAR-d-KO的HCT- 116细胞中使用VEGF和IL-8启动子-荧光素酶缺失构建体测定、EMSA和ChIP/实时PCR研究PPAR-d是否与VEGF和IL-8启动子结合以增强其转录。验证的假设可能导致开发PPAR-d靶向治疗以抑制肿瘤发生。 公共卫生相关性:蛋白过氧化物酶体增殖物激活受体δ(PPAR-d)的产生增加与结肠癌的发展有关;然而,所涉及的分子机制需要澄清。该项目旨在提高对PPAR-d促进结肠癌发展的分子机制的理解,特别是肿瘤制造新血管的能力。这种改进的理解有望帮助确定PPAR-d是否是开发治疗结肠癌新药的合适分子靶点。

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 }}

Imad Shureiqi其他文献

Imad Shureiqi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('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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    9980183
  • 财政年份:
    2016
  • 资助金额:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 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:
    $ 32.79万
  • 项目类别:

相似海外基金

How angiogenic factor induces immunosuppressive cells to tumor microenvironment
血管生成因子如何诱导免疫抑制细胞进入肿瘤微环境
  • 批准号:
    22KJ0818
  • 财政年份:
    2023
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain
腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证
  • 批准号:
    10711027
  • 财政年份:
    2021
  • 资助金额:
    $ 32.79万
  • 项目类别:
Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain
腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证
  • 批准号:
    10297199
  • 财政年份:
    2021
  • 资助金额:
    $ 32.79万
  • 项目类别:
Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain
腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证
  • 批准号:
    10625314
  • 财政年份:
    2021
  • 资助金额:
    $ 32.79万
  • 项目类别:
Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain
腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证
  • 批准号:
    10405070
  • 财政年份:
    2021
  • 资助金额:
    $ 32.79万
  • 项目类别:
Physiological role of anti-angiogenic factor thrombospondin in the regulation of endometrial function during early pregnancy in cattle
抗血管生成因子血小板反应蛋白在牛妊娠早期子宫内膜功能调节中的生理作用
  • 批准号:
    20K06385
  • 财政年份:
    2020
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Elucidation of lymphangiogenic regulatory mechanism of angiogenic factor CCN2 through tumor-associated macrophage
阐明血管生成因子CCN2通过肿瘤相关巨噬细胞的淋巴管生成调节机制
  • 批准号:
    17K11866
  • 财政年份:
    2017
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Elucidation of vascular stabilization mechanism by anti-angiogenic factor vasohibin-1
抗血管生成因子 vasohibin-1 阐明血管稳定机制
  • 批准号:
    15K20874
  • 财政年份:
    2015
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
angiogenic therapy for cerebral infarction with anti^sense homology derived peptide targeting angiogenic factor
靶向血管生成因子的反义同源肽治疗脑梗死
  • 批准号:
    15K15523
  • 财政年份:
    2015
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
The development of the anti-angiogenic factor VEGF-A165b quantification methods for cardiovascular disease.
心血管疾病抗血管生成因子 VEGF-A165b 定量方法的开发。
  • 批准号:
    26860367
  • 财政年份:
    2014
  • 资助金额:
    $ 32.79万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了