Role of fetal TCDD-activited AHR in adult heart disease

胎儿 TCDD 激活的 AHR 在成人心脏病中的作用

基本信息

批准号：
7270638
负责人：
CRAIG R TOMLINSON
金额：
$ 13.65万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270638
关键词：
Acute Adult Affinity Alleles Aryl Hydrocarbon Receptor Benzo(a)pyrene Biological C57BL/6 Mouse Carcinogens Cardiovascular Diseases Cardiovascular system Cells Chronic Data Set Development Dioxins Disease Disease Marker Dose Drug Metabolic Detoxication Ensure Environment Etiology Exposure to Fetal Development Fetus Gene Expression Genes Genetic Transcription Genomics Genotype Heart Diseases Human Incidence Knowledge Lead Ligands Link Measures Molecular Mothers Mouse Strains Mus Mutagens Myocardial Ischemia Numbers Patient currently pregnant Perinatal Exposure Personal Satisfaction Physiological Play Population Pregnancy Receptor Cross-Talk Regulation Role Signal Pathway Signal Transduction Teratogens Testing Time Tobacco smoke Toxicant exposure Variant activating transcription factor aryl hydrocarbon receptor ligand base congenic fetal insight response toxicant

项目摘要

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.

描述（由申请人提供）：拟议研究的主要目的是研究胎儿发育过程中有毒物质暴露对成人心血管（CV）系统的影响。对于因对怀孕母亲的毒性暴露而导致的成年人的心血管疾病（CVD）的病因和进展知之甚少，拟议的研究试图发现疾病的早期标志物在鉴定CVD中涉及的信号传导途径的疾病中至关重要。将检查2、3、7、8-四方氯迪本术-P-二恶英（TCDD）在CVD中从胎儿暴露中的影响。 TCDD是原型二恶英，在环境中普遍存在，并在人类中引起大量看似无关的生物学作用。 TCDD是芳基碳氢化合物受体（AHR）的最有效的配体之一，这是负责调节许多排毒基因的配体激活的转录因子。因为AHR在CV发育中起作用并与其他信号通路进行交流，并且TCDD导致成人的缺血性心脏病，并引起细胞信号传导的变化；该提议的目的是检验以下假设：胎儿中TCDD激活AHR会导致胎儿CV系统中基因表达的重编程，从而导致CVD成人发作。为了检验这一假设，提出了以下特定目标。（1）确定胎儿TCDD敏感性的窗口，以及妊娠期间TCDD激活的AHR对成人后代对CVD和CV全局转录的影响，与AHR基因座不同的小鼠菌株的CV全局转录。我们假设急性TCDD暴露对胎儿的基因组和生理作用取决于妊娠的特定时间范围内AHR的激活。（2）确定激活的AHR在妊娠期间用生物学相关剂量的TCDD治疗后，激活的AHR对成人后代的CV系统的影响。我们假设生物学相关剂量的TCDD对胎儿的基因组和生理作用在成人CVD中起着很大的作用。我们希望将急性和基于慢性的TCDD暴露的基因概况与特定的CVD联系起来，并将我们的数据集与其他基因分析数据集集成在一起。结果将导致对导致成人疾病的胎儿暴露引发的机制有更清晰的了解，并且凭借这种知识，可以开始实施预防措施以保护母亲和胎儿。