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.

Project Narrative Our research demonstrates expression of RAGE and the manifestation of its pro-inflammatory effects in exposed lung, placentas and gestating fetuses. The goal of this project is to understand the process whereby secondhand smoke and eCigarettes compromise lung and leads compromised placental development and function in order to clarify health effects of RAGE signaling during exposure. Aims in this proposal are also designed to evaluate the efficacy of SAGEs, small anti-inflammatory glycosaminoglycan derivatives that may target RAGE signaling and therapeutically ameliorate placental compromise and long-term health outcomes.