Transplacental Chemoprevention of Lung Tumors and Lymphomas

我们的目标是加强先前确定的优势，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。我们研究阻断机制和风险VS受益于母亲和胎儿的表观遗传学要求项目之间的紧密整合。只有在其他项目和核心的参与下，范围才有可能。中心假设是萝卜硫素（SFN）和吲哚-3-甲醇（I3 C）是PAH-经胎盘淋巴瘤、肺癌、肝癌和卵巢癌模型中的化学预防剂，与天然食物一样。机制是阻断和/或表观遗传，程度取决于植物化学物质。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个综合目标来测试这些假设，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。志愿者的试验利用了加速器质谱（AMS）的显着灵敏度。 具体目标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I3 C和SFN暴露的窗口;测试启动后抑制;利用肺和肝脏特异性模型;确定nrf 2信号传导在基因剂量研究中的作用;并测试F2代中的经胎盘癌症化学预防。具体目标2：完全专注于具有已知靶点（CYP 1B 1）的表观遗传学，其次是p21，gstp 1和cyclind 2，与项目1和3共同的有希望的靶点。具体目标3：利用AMS确定人体中非致癌PAH的药代动力学以及I3 C预处理的影响。评估I3 C衍生物的生物利用度，并将I3 C与全食物（布鲁塞尔芽菜）进行比较。这是一个高度转化的目标，作为进一步研究PAH暴露和经胎盘化学预防的前奏。该项目与其他两个项目高度整合，因为我们将为两者提供组织，作为回报，将能够确定小鼠和人类之间化学预防机制的相似性和差异。

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.