The effects of endogenous and dietary estrogens on colonic stem cells

内源性和膳食雌激素对结肠干细胞的影响

• 批准号: 8507640
• 负责人: Clinton D Allred
• 金额: $ 17.54万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507640
• 关键词: Address; Adult; Animals; Apoptosis; BAX gene; Cancer Patient; Cancerous; Carcinogen exposure; Carcinogens; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chemoprevention; Chemoprotective Agent; Chronic; Clinical Data; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Consumption; DNA Damage; Data; Development; Diagnostic Neoplasm Staging; Diet; Environmental Risk Factor; Epidemiology; Estradiol; Estrogen Therapy; Estrogens; Event; Evolution; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genistein; Goals; Human; In Vitro; Induction of Apoptosis; Inflammation; Internal Ribosome Entry Site; Intestinal Cancer; Intestines; Knockout Mice; LacZ Genes; Lead; Lesion; Location; Longitudinal Studies; Malignant - descriptor; Mediating; Mediator of activation protein; Meta-Analysis; Molecular; Molecular Target; Multipotent Stem Cells; Mus; Mutation; Neoplasm Metastasis; Non-Malignant; PMAIP1 gene; Physiological; Phytoestrogens; Plants; Premalignant; Prevention; Recommendation; Relative (related person); Risk; Role; Route; Signal Transduction; Staging; Stem cells; Tumor stage; Woman; adult stem cell; base; bioactive food component; cancer cell; cancer prevention; cancer risk; clinically relevant; colon carcinogenesis; colonic crypt; in vivo; innovation; interest; mouse model; novel; research study; response; self-renewal; soy; stem; stem cell biology; stem cell niche; stem cell population; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Our data support the hypothesis that endogenous estrogen (E2) or a chemoprotective diet containing estrogenic compounds reduce the risk of colon tumor development. This is consistent with human studies demonstrating that exposure to estrogen in the colon protects against malignant transformation. Although there are concerns related to estrogen therapy, dietary phytoestrogens may provide a suitable alternative. Indeed, epidemiological data suggest that soy, containing phytoestrogens such as genistein (Gen), reduces colon cancer risk. With respect to putative targets, "adult" somatic stem cells of the colon are of particular interest because they sustain self-renewal and are target cells for cancer initiating mutations. Recent evidence indicates that normal intestinal stem/progenitor cells can initiate colon tumorigenesis and drive cancer progression towards metastasis. Unfortunately, to date, the effects of endogenous and dietary estrogens on intestinal stem cell signaling has not been determined. Since estrogenic compounds can impact genes/mediators that regulate the colon stem cell niche and tumor evolution, e.g. p53 signature, our overall goal is to further elucidate how E2 and dietary Gen modulate colonic stem cells at distinct stages of malignant transformation. Based on our experimental findings, we propose two specific aims to determine how endogenous (E2) and dietary estrogen (Gen) impact multipotent stem cells in the colon. Aim 1 will use highly novel stem cell specific Lgr5-LacZ and Lgr5-EGFP mice to quantify the number and spatio-temporal location of stem cells, DNA damage and targeted apoptosis in the colonic crypt at the initiation and tumor stages of colon carcinogenesis following exposure to endogenous and diet-derived estrogens. Aim 2 will use Lgr5-stem cell targeted p53 null mice (Lgr5-EGFP-IRES-creERT2 x p53flox/flox) to define the molecular role of p53 in mediating the effects of E2 and Gen in intestinal stem cells. The proposed studies are highly innovative and will explore the physiological actions of dietary estrogenic compounds on multipotent stem cells in the colon.

描述（由申请人提供）：我们的数据支持以下假设：内源性雌激素（E2）或含有雌激素化合物的化学保护饮食可降低结肠肿瘤发生的风险。这与人体研究一致，表明结肠中暴露于雌激素可以防止恶性转化。尽管存在与雌激素治疗相关的担忧，但膳食植物雌激素可能提供合适的替代方案。事实上，流行病学数据表明，含有金雀异黄素 (Gen) 等植物雌激素的大豆可以降低结肠癌风险。就假定的靶标而言，结肠的“成年”体干细胞特别令人感兴趣，因为它们维持自我更新并且是癌症引发突变的靶细胞。最近的证据表明，正常的肠道干/祖细胞可以启动结肠肿瘤发生并驱动癌症进展至转移。不幸的是，迄今为止，内源性雌激素和膳食雌激素对肠道干细胞信号传导的影响尚未确定。由于雌激素化合物可以影响调节结肠干细胞生态位和肿瘤进化的基因/介质，例如， p53 特征，我们的总体目标是进一步阐明 E2 和膳食 Gen 如何在恶性转化的不同阶段调节结肠干细胞。根据我们的实验结果，我们提出了两个具体目标来确定内源性 (E2) 和膳食雌激素 (Gen) 如何影响结肠中的多能干细胞。目标 1 将使用高度新颖的干细胞特异性 Lgr5-LacZ 和 Lgr5-EGFP 小鼠来量化暴露后结肠癌发生起始阶段和肿瘤阶段的结肠隐窝中干细胞的数量和时空位置、DNA 损伤和靶向细胞凋亡内源性和饮食来源的雌激素。目标 2 将使用 Lgr5 干细胞靶向 p53 缺失小鼠 (Lgr5-EGFP-IRES-creERT2 x p53flox/flox) 来定义 p53 在介导肠道干细胞中 E2 和 Gen 的作用中的分子作用。拟议的研究具有高度创新性，将探讨膳食雌激素化合物对结肠多能干细胞的生理作用。