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。重点仍然是与项目1和3集成以解决机制的移植化学预防模型的发展。我们研究了阻塞机制和风险与对母亲和胎儿的好处，重点是表观遗传学，要求在项目之间进行紧密整合。只有在其他项目和核心的参与下才有可能范围。中心假设是硫烷（SFN）和吲哚-3-甲醇（I3C），是化学预防剂，在PAH转移淋巴瘤，肺，肝脏和卵巢癌模型中，全食物也是整个食品。机制是阻塞和/或表观遗传学，该度取决于植物化学化学。专注于相同的植物化学物质增强整合和协同作用。我们通过追求3个综合目的从怀孕小鼠的发现和机械研究发展到一项小型人类试验来检验假设。通过使用“人性化”小鼠，也可以增强翻译性质。与人类志愿者的试验利用了加速器质谱（AMS）的显着灵敏度。特定目的1：测试人源化小鼠的反应；检查130个剂量反应并将纯化的植物化学物质（在人类饮食水平）与全食物进行比较；测试母体饮食I3C和SFN暴露的窗户；测试抑制后抑制；利用肺和肝特异性模型；确定NRF2信号在基因剂量研究中的作用；并测试F2一代中的移植癌化学预防。具体目的2：完全关注具有已知靶标（CYP1B1）的表观遗传学，其次是P21，GSTP1和CyclInd2，这与项目1和3的共同目标是有希望的目标。具体目的3：利用AMS来确定人类非肉欲PAH的药代动力学和I3C预防量的非ca骨PAH。评估I3C衍生物的生物利用度，并将I3C与整个食物（Broussels芽）进行比较。这是一个高度转化的目的，是对PAH暴露和移植化学预防的进一步研究的前奏。该项目与其他2个高度整合在一起，因为我们将向两者提供组织，作为回报，将能够确定小鼠和人之间化学预防机制的相似性和差异。