Environmental Toxicants in Fetal Basis of Adult-onset Stroke

成人中风胎儿基础中的环境毒物

• 批准号: 7229935
• 负责人: Victoria L Herrera
• 金额: $ 19.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229935
• 关键词: Adult; Affect; Age-Months; Air; Animal Model; Barker Hypothesis; Blood - brain barrier anatomy; Brain; Brain hemorrhage; Brain region; Budgets; CDKN1A gene; Cerebellum; Cerebral hemisphere hemorrhage; Clinical; Complex; Coronary Arteriosclerosis; Data; Detection; Disease; Doctor of Medicine; Dose; Embryo; Encephalopathies; End Point; Endothelial Cells; Environment; Environmental Impact; Environmental Pollutants; Event; Experimental Designs; Exposure to; Female; Fetus; Functional disorder; Future; Gender; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Guidelines; Human; Hyperlipidemia; Hypertension; Individual; Investigation; Kidney; Mercury; Modeling; Molecular; NIH Program Announcements; Neutrophil Activation; Onset of illness; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Perinatal Exposure; Predisposition; Prevention; Public Health; Purpose; Rattus; Research; Research Personnel; Research Proposals; Resistance; Risk; Risk Factors; Role; Severities; Smoking; Staging; Stroke; Technology; Terminology; Testing; Toxic Environmental Substances; Transgenic Organisms; United States National Institutes of Health; Victoria Austrailia; Water Pollutants; base; day; environmental agent; fetal; fetal lead exposure; fetal programming; functional genomics; genetic analysis; hypercholesterolemia; in utero; insight; lead exposure; lead ion; male; neutrophil; oncoprotein p21; postnatal; response

DESCRIPTION (provided by applicant): In response to PAR-04-104: "The Fetal Basis of Adult Disease: role of the environment" aimed at the application of high-throughput functional-genomic technologies to understand which and how environmental agents contribute to currently unsuspected in-utero exposures that cause permanent functional changes that are not overtly teratogenic yet result in increased susceptibility to disease/dysfunction later in adulthood, and given research data by others showing susceptibility of brain microvasculature to subtoxic Pb-levels, and our preliminary data validating two rat models of fetal basis of adult-onset stroke (cerebral hemorrhage subtype) FeBAD(STROKE), our research proposal aims to test the hypothesis that fetal subtoxic-Pb exposure results in brain microvascular endothelial changes, which in individuals with stroke risk factors, such as hypertension and/or hypercholesterolemia, exacerbate said risk for adult-onset stroke. Accordingly, the following specific aims are prioritized to examine causal effects of fetal Pb-exposure. Aim 1. Determine whether dose-response effects of fetal exposure to subtoxic Pb-levels (10 mu g/dl, 20 mu g/dl, 40 mu g/dl) exacerbates risk for adult-onset hemorrhagic stroke in two FeBAD(STROKE) rat models: 1) transgenic (hypercholesterolemia + hypertension) and 2) nontransgenic (hypertension alone) rat models, comparing female and male rats by analyzing: a. disease course: degree of hypertension and hyperlipidemia, levels of cellular and circulating markers of endothelial dysfunction and neutrophil activation at pre-stroke stage (2-,3-months of age), and b. disease end-point: onset and severity of hemorrhagic stroke. Aim 2. In accordance with PAR guidelines for high throughput genomics-based analysis, we will determine the effects of subtoxic Pb-exposure on cortical and cerebellar transcription profiles in both transgenic and non-transgenic FeBAD-stroke rat models at embryonic E18.5 and postnatal p21 days. We prioritized transcription profile analysis of cortex and cerebellum to enhance detection of contrasting gene expression changes, since the cortex is a stroke-sensitive brain region, whereas the cerebellum is a relatively stroke- resistant brain region. Briefly, these studies will determine whether fetal programming induced by subtoxic lead exposure exacerbates FeBAD-adult-onset hemorrhagic stroke (Aim 1) and provide key insight into possible pathogenic gene networks (Aim 2). Determining the impact of environmental toxicants, such as Pb, on fetal basis of adult-onset diseases is imperative from a public health prevention perspective. Determination of interactions between environmental toxicant and fetal basis of complex diseases needs to be done prior to any genetic analysis. Currently, environmental subtoxicant-induced fetal programming is not factored in as confounder in genetic studies of susceptibility to complex multifactorial diseases.

DESCRIPTION (provided by applicant): In response to PAR-04-104: "The Fetal Basis of Adult Disease: role of the environment" aimed at the application of high-throughput functional-genomic technologies to understand which and how environmental agents contribute to currently unsuspected in-utero exposures that cause permanent functional changes that are not overtly teratogenic yet result in increased susceptibility to disease/dysfunction later in adulthood, and given其他人的研究数据表明，脑微举行对下毒性PB级的敏感性，以及我们的初步数据验证了两种大鼠成人中风的胎儿基础（脑出血亚型）FEBAD（Stroke）Febad（Stroke）的效率作为高血压和/或高胆固醇血症，加剧的人说成人中风的风险。因此，优先考虑以下特定目标以检查胎儿PB暴露的因果作用。目的1。确定胎儿暴露于潜毒PB级（10 mu g/dl，20 mu g/dl，20 mu g/dl，40 mu g/dl）是否会加剧成人出血性中风的风险，以造成两种成人出血性中风（stroke）在两种Febad（Stroke）大鼠模型：1）跨基因（1）跨基因 +超固醇 +超固定型（超级级别）和2型（Hypolentersen + Hyperseriense）和2（2）大约2）通过分析比较雌性和雌性大鼠：疾病病程：高血压和高脂血症，内皮功能障碍的细胞和循环标记水平以及中风前（2个月大的年龄）和b。疾病终点：出血性中风的发作和严重程度。 AIM 2。根据针对基于高通量基因组学分析的PAR指南，我们将确定在转基因和非转基因的Febad-Stroke大鼠模型对胚胎E18.5和非转基因大鼠模型对皮质和小脑转录谱的影响。我们优先考虑对皮质和小脑的转录谱分析，以增强对比鲜明的基因表达变化的检测，因为皮层是中风敏感的大脑区域，而小脑则是相对耐卒中的大脑区域。简而言之，这些研究将确定胎儿编程是通过无毒铅暴露诱导的，加剧了febad-Adult-Adult-Adult-Ab-Adult-Adult-Adult-Adult-Adult-Adult-Adult-Aptoss-toss-Atset-Atset-Atement-Ats-Atement-Ats-Atement-Ats-Atement-Ats-Atement-Aptoseming（AIM 1）并提供了对可能的致病基因网络的关键见解（AIM 2）。从公共卫生预防的角度来看，必须确定环境有毒物质（例如PB）对胎儿疾病的影响。在进行任何遗传分析之前，需要进行复杂疾病的环境有毒物质与胎儿基础之间的相互作用的确定。当前，在对复杂多因素疾病易感性的遗传研究中，尚未将环境下毒剂诱导的胎儿编程作为混杂因素。