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 胎盘并发症影响多达15%的妊娠，是早产发病率和死亡率的显著原因。 除了围产期的危害，包括围产期缺氧和窒息，脑性瘫痪和持续性 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显著原因。过去的研究发现，受体是一种 晚期糖基化终产物(RAGE)作为一种烟雾诱导的模式识别受体，具有强大的促吸烟活性。 炎症特征。进一步的研究表明，在以下情况下，肺和胎盘中的愤怒会增加 二手烟或eCig暴露以及有条件上调愤怒表现转基因小鼠 吸烟者的肺部和在没有吸烟的情况下胎盘功能不全的特征。鼠尾草是半合成的 在许多人类疾病的动物模型中，糖胺葡聚糖醚是炎症的有效调节剂， 并处于牙周炎、口腔粘膜炎和膀胱炎的临床前开发阶段。重要的是，圣人 显著抑制RAGE与其信号转导所必需的许多配体之间的相互作用。目前的建议 目的是彻底评估RAGE作为暴露胎盘的分子靶点的生物学，并考虑母体 肺部和全身炎症的协调期间的并发症。这项提议的一个关键创新是 控制愤怒表达的动物模型的集合，包括愤怒零的小鼠。这项建议还具有 由于其临床翻译潜力可改善吸烟或eCig蒸气诱导的炎症，因此具有显著影响 和胎盘功能障碍。中心假设是抑制RAGE信号可以改善肺和胎盘 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 使用本科生使用的先进分子方法来测试我们的假设。这些研究 本提案中概述的将验证RAGE信号作为转化性预防或 不能或不愿去除烟草暴露的人的胎盘缺陷的减轻，但也可能有助于 阐明RAGE在许多生理过程中介导的发病机制。

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.