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

基本信息

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
项目类别：
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

项目摘要

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减少结肠肿瘤发育的风险。这与人类的研究一致，该研究表明，结肠中暴露于雌激素可以预防恶性转化。尽管存在与雌激素疗法有关的问题，但饮食中的植物雌激素可能会提供合适的选择。实际上，流行病学数据表明，大豆含有植物源（Gen）等植物雌激素，可降低结肠癌的风险。关于假定的靶标，结肠的“成人”体细胞特别感兴趣，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，正常的肠干/祖细胞可以启动结肠肿瘤发生并促进癌症向转移的进展。不幸的是，迄今为止，尚未确定内源性和饮食中雌激素对肠道干细胞信号传导的影响。由于雌激素化合物会影响调节结肠干细胞生态位和肿瘤进化的基因/介体，例如p53签名，我们的总体目标是进一步阐明在恶性转化的不同阶段E2和饮食中如何调节结肠干细胞。根据我们的实验发现，我们提出了两个具体目的，以确定内源性（E2）和饮食中的雌激素（Gen）如何影响结肠中的多能干细胞。 AIM 1将使用高度新颖的干细胞特异性LGR5-LACZ和LGR5-EGFP小鼠来量化干细胞的数量和时空位置，在结肠癌的起始和肿瘤阶段的结肠隐窝中的DNA损伤和靶向凋亡。 AIM 2将使用靶向P53 NULL小鼠（LGR5-EGFP-IRES-CREERT2 X P53FLOX/FLOX）来定义p53在介导E2和Gen在肠道干细胞中的作用中的分子作用。拟议的研究具有高度创新性，将探索饮食中雌激素化合物对结肠多能干细胞的生理作用。