Transplacental Chemoprevention of Lung Tumors and Lymphomas

肺肿瘤和淋巴瘤的经胎盘化学预防

• 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
• 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

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点 (CYP1B1) 的表观遗传学，然后是 p21、gstp1 和 cyclind2，这些有前景的靶点与项目 1 和 3 相同。具体目标 3：利用 AMS 确定人类非致癌性 PAH 的药代动力学以及 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。