Role of fetal TCDD-activited AHR in adult heart disease

描述（由申请人提供）：拟议研究的主要目的是研究胎儿发育期间毒物暴露对成人心血管（CV）系统的影响。由于孕妇接触有毒物质导致成人心血管疾病（CVD）的病因和进展尚不清楚，拟议的研究旨在揭示疾病的早期标志物，这些标志物对识别CVD相关信号通路至关重要。胎儿接触2,3,7,8 -四氯二苯并-对二恶英（TCDD）对CVD的影响将被检查。TCDD是典型的二恶英，在环境中普遍存在，并对人类造成大量看似无关的生物效应。TCDD是芳烃受体（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。因为AHR在心血管发展中起作用并与其他信号通路交叉对话，因为TCDD在成人中引起缺血性心脏病并诱导细胞信号通路的变化；本研究的目的是验证一种假设，即TCDD在胎儿体内激活AHR会导致胎儿CV系统中基因表达的重编程，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敏感性的窗口期，以及妊娠期TCDD激活的AHR对AHR位点不同小鼠品系成年后代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妊娠特定时间内AHR的激活。(2)确定在妊娠期使用生物相关剂量的TCDD治疗后，活化AHR对成年后代CV系统的影响。我们假设TCDD对胎儿的生物学相关剂量的基因组和生理效应在成人CVD中起重要作用。我们希望将急性和慢性TCDD暴露与特定cvd的基因图谱联系起来，并将我们的数据集与其他基因图谱数据集整合起来。研究结果将使我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，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.