Role of fetal TCDD-activited AHR in adult heart disease

描述(申请人提供)：拟议研究的主要目标是研究胎儿发育期间毒物暴露对成人心血管系统的影响。由于孕妇对毒物的暴露，成人心血管疾病(CVD)的病因和进展知之甚少，拟议的研究试图揭示疾病的早期标志物，这对识别CVD所涉及的信号通路至关重要。2，3，7，8-四氯二苯并-对二恶英(TCDD)在胎儿暴露所致脑血管病中的作用将被研究。TCDD是典型的二恶英，广泛存在于环境中，对人类造成大量看似无关的生物效应。TCDD是芳香烃受体(AHR)最有效的配体之一，AHR是一种配体激活的转录因子，负责调节许多解毒基因。由于AHR在血管紧张素转换酶的形成和与其他信号通路的相互作用，以及TCDD在成人中引起缺血性心脏病和诱导细胞信号的改变；本研究的目的是验证这样一种假设，即TCDD在胎儿激活AHR导致胎儿血管紧张素转换酶系统的基因表达重新编程，从而导致成人心血管疾病的发生。为了验证这一假设，提出了以下具体目标。(1)确定胎儿TCDD敏感性的窗口以及妊娠期间TCDD激活的AHR对不同AHR基因座小鼠成体后代CVD和CV全局转录的影响。我们假设，急性TCDD暴露对胎儿的基因组和生理影响取决于特定孕期内AHR的激活。(2)在孕期给予生物剂量的TCDD后，确定激活的AHR对成年子代CV系统的影响。我们推测，生物相关剂量的TCDD对胎儿的基因组和生理效应在成人CVD中发挥着重要作用。我们希望将急性和慢性TCDD暴露的基因图谱与特定的心血管疾病联系起来，并将我们的数据集与其他基因图谱数据集整合在一起。这一结果将使人们更清楚地了解胎儿暴露导致成人疾病的机制，有了这些知识，就可以开始实施预防措施来保护母亲和胎儿。

DESCRIPTION (provided by applicant): The primary objective of the proposed studies is to study the effects of toxicant exposures during fetal development on the adult cardiovascular (CV) system. Little is known of the etiology and progression of cardiovascular disease (CVD) in adults resulting from toxicant exposures to the pregnant mother, and the proposed studies seek to uncover early markers of disease vital in the identification of signaling pathways involved in CVD. The effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in CVD from fetal exposure will be examined. TCDD, the prototypical dioxin, is pervasive in the environment and causes a large number of seemingly unrelated biological effects in humans. TCDD is one of the most potent ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsible for the regulation of many detoxification genes. Because the AHR plays a role in CV development and cross talks with other signaling pathways, and because TCDD causes ischemic heart disease in the adult and induces changes in cell signaling; the intent of this proposal is to test the hypothesis that activation of the AHR by TCDD in the fetus causes a reprogramming of gene expression in the fetal CV system that results in the adult onset of CVD. To test this hypothesis, the following specific aims are proposed. (1) Determine the window of fetal TCDD sensitivity and the effect that the TCDD-activated AHR during gestation has on CVD and CV global transcription of adult progeny from mouse strains that differ at the Ahr locus. We hypothesize that the genomic and physiological effects of an acute TCDD exposure on the fetus are dependent on the activation of the AHR during particular time frames of gestation. (2) Determine the effect of the activated AHR on the CV system of adult progeny following treatment with biologically relevant doses of TCDD during gestation. We hypothesize that the genomic and physiological effects of biologically relevant doses of TCDD on the fetus play a large role in adult CVD. We expect to link gene profiles of acute- and chronic-based TCDD exposures to specific CVDs and to integrate our data sets with other gene profiling data sets. The results will lead to a clearer understanding of the mechanisms that are initiated from fetal exposures that lead to adult disease, and with such knowledge, preventative measures can begin to be implemented to protect mother and fetus.