Receptor for advanced glycation end-products signaling induction in the lung and placenta due to secondhand smoke and e-cigarette vapor

项目摘要 胎盘并发症影响高达15%的所有妊娠，是早产发病率和死亡率的一个显着原因。 除了围产期的危害，包括围产期缺氧和窒息，脑瘫，和持续性 新生儿肺动脉高压，妊娠并发症的长期后遗症包括成人高血压， 肺部并发症心脏病中风和糖尿病非自愿接触烟草烟雾或电子产品 香烟被认为是胎盘异常的一个显著致病因素。过去的研究确定了 晚期糖基化终末产物（Advanced Glycation End-products，简称AGEs）是一种烟雾诱导的模式识别受体， 炎症特征。进一步的研究表明， 二手烟或电子烟暴露以及条件性上调ECO 2基因的转基因小鼠表现出 吸烟者的肺和胎盘功能不全的标志在没有烟雾的情况下。SAGE是半合成的 糖胺聚糖醚在许多人类疾病的动物模型中是有效的炎症调节剂， 并处于牙周炎、口腔粘膜炎和膀胱炎的临床前开发中。重要的是，SAGE 显著抑制信号传导所必需的β-内酰胺酶及其许多配体之间的相互作用。现时的建议 目的是彻底评估胎盘暴露中作为分子靶点的胎盘的生物学，并考虑母体 在并发症的编排过程中肺部和全身炎症。该提案的一个关键创新是 一组控制EST 3表达的动物模型，包括EST 3缺失小鼠。该提案还具有 由于其改善吸烟或eCIG蒸汽诱导的炎症的临床转化潜力， 和胎盘功能障碍核心假设是抑制BMP 2信号传导可以改善肺和胎盘 生长/功能，并保护后代免受暴露的影响。提出了两个具体目标，每个目标 使用本科生采用的先进分子方法来测试我们的假设。研究 本提案中概述的方法将验证作为翻译预防的靶向途径的β-淀粉样蛋白信号传导， 减轻不能或不愿消除烟草暴露的个体的胎盘缺陷，但也可能有助于 阐明RAGE介导的发病机制在一些生理过程。

Project Summary Placental complications affect up to 15% of all pregnancies and is a notable cause of preterm morbidity and mortality. In addition to perinatal compromises including perinatal hypoxia and asphyxia, cerebral palsy, and persistent pulmonary hypertension of the newborn, long-term sequelae of gestational complications include adult hypertension, pulmonary complications, heart disease, stroke and diabetes. Involuntary exposure to tobacco smoke or electronic cigarettes is assumed to be a notable causative factor of placental anomalies. Past studies identified the receptor for advanced glycation end-products (RAGE) as a smoke-induced pattern recognition receptor with potent pro- inflammatory characteristics. Further research demonstrated that RAGE is increased in the lung and placenta following secondhand smoke or eCig exposure and that transgenic mice that conditionally up-regulate RAGE manifest aspects of a smoker’s lung and hallmarks of placental insufficiency in the absence of smoke. SAGEs are semi-synthetic glycosaminoglycan ethers that are potent modulators of inflammation in numerous animal models of human disease, and are in preclinical development for periodontitis, oral mucositis, and bladder inflammation. Importantly, SAGEs significantly inhibit interactions between RAGE and its many ligands necessary for signaling. The present proposal aims to thoroughly assess the biology of RAGE as a molecular target in exposed placenta and to consider maternal pulmonary and systemic inflammation during the orchestration of complications. A key innovation of this proposal is a collection of animal models that control RAGE expression including RAGE null mice. This proposal also has significant impact due to its clinical translational potential to ameliorate smokeor eCIG vapor-induced inflammation and placental dysfunction. The central hypothesis is that inhibition of RAGE signaling improves lung and placental growth/function and protects the offspring from the effects of exposure. Two specific aims are proposed, and each uses advanced molecular methodologies employed by undergraduate students to test our hypotheses. The studies outlined in this proposal will validate RAGE signaling as a target pathway for the translational prevention or attenuation of placental defects in individuals unable or unwilling to remove tobacco exposure but may also help to clarify RAGE-mediated pathogenesis in a number of physiological processes.