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

二手烟和电子烟蒸汽导致肺和胎盘中晚期糖基化终产物信号诱导的受体

基本信息

批准号：
10437516
负责人：
JUAN A ARROYO
金额：
$ 45.45万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-13 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437516
关键词：
Adult Adverse effects Affect Animal Model Animals Anti-Inflammatory Agents Apoptosis Asphyxia Neonatorum Behavior Biology Bladder Cells Cerebral Palsy Characteristics Clinical Collection Data Defect Diabetes Mellitus Disease Electronic Nicotine Delivery Systems Electronic cigarette End Point Assay Ethers Exposure to Faculty Family Fetus Functional disorder Gene Expression Glycosaminoglycans Goals Grant Growth Health Heart Diseases Histologic Human Hypertension IgG Receptors In Vitro Individual Inflammation Inflammatory Inflammatory Response Institution Knockout Mice Life Ligands Link Lung Mediating Metabolic Metabolism Methodology Modeling Modernization Molecular Molecular Biology Molecular Target Morbidity - disease rate Mothers Mus Newborn Infant Nose Outcome Pathogenesis Pathway interactions Pattern recognition receptor Perinatal Perinatal Hypoxia Periodontitis Physiological Physiological Processes Placenta Placental Insufficiency Placentation Polysaccharides Population Positioning Attribute Pregnancy Prevalence Prevention Process Pulmonary Inflammation Receptor Inhibition Research Resources Role Science Signal Induction Signal Transduction Small Interfering RNA Smoke Smoker Smoking Stroke Students Sulfate Symptoms Techniques Testing Therapeutic Tobacco Tobacco use Training Transgenic Mice Villus Weight attenuation cigarette smoke cigarette smoking cytokine design e-cigarette aerosols efficacy evaluation environmental tobacco smoke environmental tobacco smoke exposure exhaustion experience exposure to cigarette smoke fetal human disease human model improved in vivo Model innovation lipophilicity long-term sequelae member mortality mouse model neonatal pulmonary hypertension novel obstetrical complication offspring oral mucositis postnatal preclinical development prenatal preventable death receptor expression receptor for advanced glycation endproducts response skills systemic inflammatory response therapeutic target tobacco exposure translational potential trend trophoblast undergraduate student vapor

项目摘要

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.

项目概要胎盘并发症影响高达 15% 的妊娠，是早产发病率和死亡率的一个重要原因。除了围产期危害外，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。过去的研究发现，香烟被认为是胎盘异常的一个显着致病因素。晚期糖基化终产物（RAGE）作为烟雾诱导的模式识别受体，具有有效的促进一步的研究表明，RAGE 在肺部和胎盘中增加。二手烟或电子烟暴露以及有条件上调 RAGE 的转基因小鼠表现出以下几个方面在没有烟雾的情况下，吸烟者肺部的症状和胎盘功能不全的标志是半合成的。糖胺聚糖醚是许多人类疾病动物模型中炎症的有效调节剂，并正在针对牙周炎、口腔粘膜炎和膀胱炎症进行临床前开发。重要的是，SAGE。显着抑制 RAGE 及其许多信号传导所需的配体之间的相互作用。旨在彻底评估 RAGE 作为暴露胎盘分子靶点的生物学特性，并考虑母体该提案的一个关键创新是并发症发生过程中的肺部和全身炎症。该提案还包括控制 RAGE 表达的动物模型集合，包括 RAGE 缺失小鼠。由于其改善吸烟或 eCIG 蒸汽引起的炎症的临床转化潜力而产生重大影响核心假设是抑制 RAGE 信号可改善肺和胎盘功能。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。使用本科生采用的先进分子方法来检验我们的假设。该提案中概述的将验证 RAGE 信号传导作为转化预防或无法或不愿意消除烟草暴露的个体胎盘缺陷的减轻，但也可能有助于 RAGE 介导的发病机制在许多生理过程中得到阐明。