Impact of benzene-induced MIA on fetal T cell development

苯诱导的 MIA 对胎儿 T 细胞发育的影响

• 批准号: 10605881
• 负责人: GIL G MOR
• 金额: $ 38.71万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-13 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605881
• 关键词: 2019-nCoV; Abbreviations; Address; Affect; Air Pollutants; Air Pollution; Area; Asthma; B-Lymphocytes; Benzene; Biological; Child; Chronic Disease; Cities; Clinical; Communicable Diseases; Decidua; Development; Ebola; Equilibrium; Exposure to; Fetal Development; Fetal Growth Retardation; Fetal health; Fetus; Future; Growth and Development function; Health; Homing; Immune; Immune response; Immune system; Incidence; Industrialization; Infant; Infection; Inflammation; Inflammatory; Life; Link; Liver; Maternal Exposure; Modeling; Modification; Molecular; Nature; Neonatal; Outcome; Outcome Study; Pathogenesis; Phenotype; Placenta; Pre-Eclampsia; Predisposition; Pregnancy; Pregnancy Complications; Premature Birth; Process; Property; Resolution; Severities; Signal Pathway; Signal Transduction; Site; Soil; Superfund; T cell differentiation; T-Cell Development; T-Lymphocyte; Testing; Thymocyte Development; Thymus Gland; Toluene; Training; Vaccines; Viral Respiratory Tract Infection; Volatilization; Xylene; ZIKA; epidemiology study; ethylbenzene; fetal; fetal programming; ground water; immune activation; implantation; in utero; male; maternal morbidity; maternal outcome; microbial; mortality; neonatal morbidity; neonate; offspring; pandemic disease; pathogen; postnatal; preclinical study; prenatal exposure; prevent; public health relevance; response; stressor; vapor intrusion; volatile organic compound

Growing evidences suggests that exposure to volatile, very volatile, and semi-volatile organic compounds (collectively abbreviated VOCs) during vulnerable life windows of susceptibility is an important determinant of maternal-fetal health, with implications for preterm birth, children sensitivity to infections, asthma and other adverse health outcomes. The central theme of this application focuses on deciphering the signaling pathways by which exposure to VOCs during pregnancy have an impact on early life growth and development with a focus on the fetal immune system. Our central hypothesis is that inflammation in the placenta and decidua due to maternal exposure to VOCs, alters the programming of the fetal immune system, which results in an aberrant post-natal immune response to respiratory viral infections. Our preliminary studies suggest that although the fetus may be protected against microbial infection, the outcome of maternal exposure, protective or deleterious, depends on the nature of the immune response and the severity of the inflammatory process at the implantation site (placenta-decidua interface). The mechanisms underlying the response of the fetal immune system and how indirect training by the maternal inflammation takes place is unclear and understudied. Our specific aims are: Aim 1. To determine the effect of VOCs maternal exposure on placental and fetal inflammation. Aim 2. To determine the impact of VOCs exposure on TLR signaling responsible for the homing and differentiation of T and B cells. Aim 3. Characterize the signals from the placenta responsible for the susceptibility to respiratory viral infections of the offspring. Upon completion of these aims we will have a better understanding of the outcomes associated with the impact of VOCs exposure on the placental/decidua unit and its consequent influence on fetal programing and its potential effects on the development of an appropriate neonatal immune responses. Adequate response to infection is the result of a delicate balance between an efficient immune response against pathogens and its quick resolution preventing widespread over-activation. The cellular and molecular components of this regulatory balance are determined during fetal development.

越来越多的证据表明，接触挥发性、高挥发性和半挥发性有机化合物 （统称挥发性有机化合物）在脆弱生命窗口期间的敏感性是一个重要的决定因素 母婴健康，对早产、儿童对感染的敏感性、哮喘和其他疾病有影响 不良的健康结果。该应用程序的中心主题侧重于破译信号通路 怀孕期间接触挥发性有机化合物会对早期生命的生长和发育产生影响 重点关注胎儿的免疫系统。我们的中心假设是胎盘和蜕膜的炎症 由于母亲接触挥发性有机化合物，会改变胎儿免疫系统的编程，从而导致 产后对呼吸道病毒感染的异常免疫反应。我们的初步研究 表明虽然胎儿可能受到保护免受微生物感染，但母体的结果 接触，无论是保护性的还是有害的，取决于免疫反应的性质和严重程度 植入部位（胎盘-蜕膜界面）的炎症过程。其背后的机制 胎儿免疫系统的反应以及母体炎症的间接训练是如何发生的 不清楚且未得到充分研究。我们的具体目标是： 目标 1. 确定母体接触 VOC 对胎盘和胎儿炎症的影响。 目标 2. 确定 VOC 暴露对负责归巢和归巢的 TLR 信号传导的影响 T 细胞和 B 细胞的分化。 目标 3. 表征胎盘对呼吸道病毒易感性的信号 感染后代。 完成这些目标后，我们将更好地了解与以下相关的结果 VOC 暴露对胎盘/蜕膜单位的影响及其对胎儿编程的后续影响 及其对适当新生儿免疫反应发展的潜在影响。足够的 对感染的反应是有效免疫反应之间微妙平衡的结果 病原体及其快速解决可防止广泛的过度激活。细胞和分子 这种调节平衡的组成部分是在胎儿发育过程中决定的。