Project 3: Human Fetal Lung, Arsenic Exposure, Tissue Remodeling

项目 3：人类胎儿肺、砷暴露、组织重塑

• 批准号: 7846632
• 负责人: MONIQUE E DEPAEPE
• 金额: $ 6.1万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846632
• 关键词: Adult; Adverse effects; Affect; Air; Arsenic; Asthma; Biological Markers; Blood; Bronchiectasis; Child; Childhood; Chronic; Coughing; Development; Disease; Distal; Drug Kinetics; Dyspnea; Ensure; Environmental Exposure; Epigenetic Process; Epithelium; Equilibrium; Etiology; Exposure to; Fetal Development; Fetal Lung; Gases; Gene Expression; Goals; Graft Survival; Growth; Human; Incidence; Lead; Link; Lung; Lung diseases; Malignant neoplasm of lung; Mediating; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Phenotype; Pilot Projects; Pregnancy; Role; Site; Staging; System; Testing; Tissues; Toxic Environmental Substances; Work; Xenograft Model; Xenograft procedure; drinking water; exposed human population; fetal; in utero; insight; lung development; lung maturation; lung xenograft; novel; offspring; postnatal; respiratory; young adult

Fetal lung development requires coordinated remodeling of pulmonary epithelium, vasculature and supporting matrix to establish an effective gas exchange system. Intrauterine and early postnatal exposure to environmental toxicants may disrupt this delicate balance and result in respiratory morbidity in children and adults. Inorganic arsenic is a ubiquitous environmental toxicant that targets the lung with both neoplasfic and non-neoplasfic endpoints. Recent evidence in mice suggests that gestafional exposure to arsenic disrupts fetal lung development and results in an asthma-like phenotype in the offspring. Studies in humans described increased incidence of bronchiectasis, dyspnea, chronic obstructive and restrictive lung disease in children and young adults exposed to arsenic in utem. This pilot project will develop and employ a human fetal lung xenograft model to determine the mechanisms of arsenic-induced disruption of human fetal lung remodeling. Our central hypothesis is: Arsenic exposure of human fetal lunq xenotransplants results in disrupted postglandular lung remodeling, mediated by molecular and epigenetic alterations. We will perform xenotransplants of 2nd trimester human fetal lungs, allowing study of human lung maturation and cytodifferentiation from pseudoglandular and canalicular stages of development. Jn Specific Aim 1. we will develop a human fetal lung xenograft model of in utero arsenic exposure. We will assess the best graft conditions, including size, site and initial stage to ensure opfimal graft survival and maturation. In addifion. we will study the pharmacokinetic relationship between arsenic exposure in the drinking water and fissue-specific distribution of arsenic and its metabolites. In Specific Aim 2. we will determine the effects of environmentally relevant levels of arsenic exposure on growth kinefics. cytodifferentiation and global gene expression in the developing human lung. Finally, in Specific Aim 3. we will determine the epigenetic modifications induced by arsenic exposure in the human xenografts. This pilot project will lead to the elucidation of molecular targets and biomaricers of inorganic arsenic exposure during lung development and may give insight into the efiology of arsenic-induced respiratory disease and lung cancers.

胎儿肺发育需要肺上皮、脉管系统和肺组织的协调重塑 支持矩阵建立有效的气体交换系统。宫内和产后早期 接触环境毒物可能会破坏这种微妙的平衡并导致呼吸道疾病 在儿童和成人中。无机砷是一种普遍存在的环境毒物，它的目标是肺部 肿瘤和非肿瘤终点。最近在小鼠身上的证据表明，妊娠期 接触砷会扰乱胎儿肺部发育，导致胎儿出现类似哮喘的表型 后代。对人类的研究表明，支气管扩张、呼吸困难、慢性 子宫内暴露于砷的儿童和年轻人的阻塞性和限制性肺病。这 试点项目将开发并采用人胎肺异种移植模型来确定其机制 砷引起的人胎肺重塑破坏。我们的中心假设是：砷 人类胎儿 lunq 异种移植物的暴露会导致腺后肺重塑破坏， 由分子和表观遗传改变介导。我们将进行第二个三个月的异种移植 人胎肺，可以研究人肺的成熟和假腺体的细胞分化 和小管的发育阶段。 Jn 具体目标 1. 我们将开发人胎肺异种移植物 子宫内砷暴露模型。我们将评估最佳移植条件，包括大小、部位和 初始阶段，以确保最佳移植物存活和成熟。另外。我们将研究 饮用水中砷暴露与组织特异性之间的药代动力学关系 砷及其代谢物的分布在具体目标 2 中，我们将确定以下效果： 环境相关的砷暴露水平对生长动力学的影响。细胞分化和全局 发育中的人肺中的基因表达。最后，在具体目标 3 中，我们将确定 人类异种移植物中砷暴露引起的表观遗传修饰。该试点项目将引领 阐明肺期间无机砷暴露的分子靶标和生物标志物 发展并可能有助于深入了解砷引起的呼吸道疾病和肺部疾病的病因学 癌症。