Transplacental Chemoprevention of Lung Tumors and Lymphomas

肺肿瘤和淋巴瘤的经胎盘化学预防

基本信息

批准号：
8732425
负责人：
David E Williams
金额：
$ 26.04万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-17 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732425
关键词：
Acetylation Acids Address Adult Age Apoptosis Area Aromatic Polycyclic Hydrocarbons Barker Hypothesis Benefits and Risks Bioavailable Biological Assay Biological Availability Biological Markers Breeding Broccoli - dietary CYP1B1 gene Cancer Model Carcinogens Cell Cycle Chemicals Chemoprevention Chemopreventive Agent Chemoprotection Colon DNA Methylation DNA Methyltransferase DNA Modification Methylases Development Diet Dietary Indole Dietary intake Discipline of Nursing Dose Drug Kinetics Environmental Health Epigenetic Process Etiology Exposure to Fetal Tissues Fetus Food Freeze Drying Gene Dosage Gene Expression General Population Generations Genes Goals Grant Green tea Histone Deacetylase Histones Human Human Milk Human Volunteers Indole-3-Carbinol Infant Isothiocyanates Knockout Mice Lactation Liver Lung Lung Lymphoma Lung Neoplasms Lymphoma Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of ovary Maternal-Fetal Exchange Methylation Modeling Monitor Mothers Mouse Strains Mus Nature Organ Outcome Ovary Phosphorylation Physical condensation Phytochemical Play Pre-Clinical Model Pregnancy Prostate Protocols documentation Pyrenes Risk Role Signal Transduction Source Staging Sulforaphane Techniques Testing Thymus Gland Time Tissues Toxic effect Transgenic Mice Transgenic Organisms Uterus Weaning Woman cancer chemoprevention carcinogenesis chlorophyllin comparative cruciferous vegetable environmental chemical epigenetic marker exposed human population in utero middle age mortality novel offspring pre-clinical pregnant programs pup research study response synergism tumor young adult

项目摘要

Our goal is to enhance strengths previously identified and eliminate weaknesses. The focus remains development of a transplacental chemoprevention model integrated with projects 1 & 3 to address mechanisms. We examine blocking mechanisms and risk VS benefit to mother and fetus with a focus on epigenetics demanding tight integration among projects. The scope is only possible with the participation of the other projects and cores. The central hypothesis is sulforaphane (SFN) and indole-3-carbinol (I3C) are chemopreventive agents, as are the whole foods, in a PAH-transplacental lymphoma, lung, liver and ovary cancer model. Mechanisms are blocking and/or epigenetic, the degree depending on the phytochemical. Focus on the same phytochemicals enhance integration and synergism. We test the hypotheses by pursuit of 3 integrated aims progressing from discovery and mechanistic studies in pregnant mice to a small human trial. The translational nature is also enhanced by use of a "humanized" mouse. The trial with human volunteers takes advantage of the remarkable sensitivity of accelerator mass spectromety (AMS). Specific Aim 1: Test the response of humanized mice; examine 130 dose-response and compare purified phytochemicals (at human dietary levels) to whole foods; test windows of maternal dietary I3C and SFN exposure; test post-initiation suppression; utilize lung- and liver-specific models; determine role of nrf2 signaling in a gene dosage study; and test transplacental cancer chemoprevention in an F2 generation. Specific aim 2: Focus entirely on epigenetics with a known target (CYP1B1), followed by p21, gstp1 and cyclind2, promising targets in common with projects 1 & 3. Specific aim 3: Utilize AMS to determine pharmacokinetics of a non-carcinogenic PAH in humans and impact of I3C pretreat. Assess bioavailability of I3C derivatives and compare I3C with the whole food (Brussels sprouts). This is a highly translational aim that serves as a prelude to further studies of PAH exposure and transplacental chemoprevention. This project is highly integrated with the other 2 as we will provide tissues to both and, in return, will be able to determine the similarities and differences of chemoprevention mechanisms between mouse and human.

我们的目标是增强先前确定的优势并消除弱点。重点仍然是开发与项目 1 和 3 相结合的经胎盘化学预防模型，以解决机制问题。我们研究了阻断机制以及对母亲和胎儿的风险与益处，重点是需要项目之间紧密整合的表观遗传学。该范围只有在其他项目和核心的参与下才可能实现。中心假设是萝卜硫素 (SFN) 和吲哚-3-甲醇 (I3C) 在 PAH 经胎盘淋巴瘤、肺癌、肝癌和卵巢癌模型中是化学预防剂，就像天然食品一样。机制是阻断和/或表观遗传，其程度取决于植物化学物质。注重同一植物化学物质增强整合和协同作用。我们通过追求 3 个综合目标来检验这些假设，从怀孕小鼠的发现和机制研究到小型人体试验。通过使用“人源化”小鼠也增强了翻译性质。人类志愿者试验利用了加速器质谱 (AMS) 卓越的灵敏度。具体目标1：测试人源化小鼠的反应；检查 130 种剂量反应并将纯化植物化学物质（在人类饮食水平）与天然食品进行比较；母亲膳食 I3C 和 SFN 暴露的测试窗口；测试启动后抑制；利用肺和肝特异性模型；确定 nrf2 信号传导在基因剂量研究中的作用；并在 F2 代中测试经胎盘癌症的化学预防。具体目标 2：完全关注具有已知靶标 (CYP1B1) 的表观遗传学，然后是 p21、gstp1 和 cyclind2，这些有前景的靶标与项目 1 和 3 相同。具体目标 3：利用 AMS 确定非致癌性 PAH 的药代动力学人类和 I3C 预处理的影响。评估 I3C 衍生物的生物利用度并将 I3C 与天然食品（抱子甘蓝）进行比较。这是一个高度转化的目标，为进一步研究 PAH 暴露和经胎盘化学预防奠定了基础。该项目与其他两个项目高度集成，因为我们将为两者提供组织，作为回报，我们将能够确定小鼠和人类之间化学预防机制的异同。