Programmatic role of maternal preconception stress on offspring metabolic health

项目摘要 非洲裔美国妇女和她们的婴儿在一年内出现病理或死亡的可能性是其他人的两倍。 即使在控制了收入、获得护理和教育的情况下，产后的女性也比白人女性多。 这种种族差异的根本原因还不清楚，但一个促成因素可能是 种族主义压力感知（PSR）种族歧视引起了一种生理压力反应， 寿命的延长会导致长期的压力状态。像慢性压力一样，PSR与对以下问题的反应受损有关： 压力、过早老化病理、慢性疾病风险增加以及累积“磨损和 身体系统上的“撕裂”或非稳态负荷。然而，在整个过程中， 妇女的一生，包括PSR，与随后的心理或生理挑战相互作用， 未知由于怀孕是一个令人难以置信的代谢需求和增加胎盘氧化和 线粒体应激是妊娠期病理如妊娠期糖尿病的关键内表型， 妊娠前的非稳态负荷可能会导致妊娠障碍的风险。我们发明了一种新型老鼠 母体孕前压力模型，其中孕前压力程序母体代谢功能障碍， 怀孕的能量需求暴露了这一点，并改变了母亲和胎儿的健康结果。激动人心 初步数据表明，在对雌性后代进行编程时， 压力失调基于这些数据，我们假设怀孕对能量的需求 潜在的母体代谢功能障碍由孕前压力编程，改变后代发育， 涉及胎盘性别特异性表观遗传重编程的孕产妇健康。指导下 主要导师Bale博士和指导委员会，概述的培训计划将使PI获得 在表观遗传学，生物信息学和代谢方面进行必要的技术和教学培训（1），以利用这一点 开展培训，以实施“组学”技术，并增进对“组学”长期方案影响的了解。 先入为主的压力（2），并加强语法，科学写作和指导技能建设， 最终目标是成为一名独立的主要研究者（3）。所有培训将在大学进行。 医学的马里兰州学校，一个主要的研究机构与国家的核心服务的巨大网络， 艺术设施和专业知识，以支持生物医学研究。三个具体目标将解决这一假设， 确定母体环境的孕前压力编程在改变后代中的作用 胎盘OGT如何整合来自母体环境的代谢信号以编程胎儿 发展（目标2），以及由于女性怀孕而加剧的孕前压力的代际后果。 后代应激超敏反应（Aim 3）。这项研究为代谢紊乱如何 风险是复杂的，在整个妇女的生命周期的孕前压力，包括PSR，并具有长期的 母亲和后代的健康后果，这一过程可能导致更大的种族健康差距。

Project Summary African-American women and their infants are twice as likely to experience pathologies or die up to one year postpartum than their Caucasian counterparts, even when controlling for income, access to care, and education. The underlying cause of this racial disparity is not well understood, but one contributing factor may be the perceived stress of racism (PSR). Racial discrimination evokes a physiological stress response and across the lifespan precipitates a state of chronic stress. Like chronic stress, PSR is associated with impaired responses to stress, premature aging pathologies, increased risk of chronic diseases, and increased cumulative “wear and tear” on body systems, or allostatic load. However, the mechanisms by which stress experience throughout a woman’s lifetime, including PSR, interacts with subsequent psychological or physiological challenges are unknown. As pregnancy is a time of incredible metabolic demands and increased placental oxidative and mitochondrial stress are key endophenotypes of gestational pathologies like gestational diabetes, increased allostatic load prior to pregnancy may contribute to gestational disorder risk. We have developed a novel mouse model of maternal preconception stress, where preconception stress programs maternal metabolic dysfunction, unmasked by the energetic demands of pregnancy, and alters maternal and fetal health outcomes. Exciting preliminary data implicates sex-specific epigenetic changes in the placenta in programming female offspring stress dysregulation. Based on these data, we hypothesize that the energetic demands of pregnancy unmask latent maternal metabolic dysfunction programmed by preconception stress, altering offspring development and maternal health involving sex-specific epigenetic reprogramming of the placenta. Under the guidance of the primary mentor, Dr. Bale, and mentoring committee, the outlined training plan will allow the PI to gain the necessary technical and didactic training in epigenetics, bioinformatics, and metabolism (1), to leverage this training to implement ‘omics technology and advance knowledge on the long-term programmatic effects of preconception stress (2), and enhance grantsmanship, scientific writing, and mentorship skills building towards the ultimate goal of becoming an independent Principal Investigator (3). All training will occur at the University of Maryland School of Medicine, a major research institution with a vast network of core services with state-of-the- art facilities and expertise to support biomedical research. Three Specific Aims will address this hypothesis by determining the role of preconception stress programming of the maternal milieu in altering offspring development (Aim 1), how placental OGT integrates metabolic signals from the maternal milieu to program fetal development (Aim 2), and the intergenerational consequences of preconception stress compounded by female offspring stress hypersensitivity (Aim 3). This research provides mechanistic insight into how metabolic disorder risk is compounded throughout a woman’s lifespan by preconception stress, including PSR, and has long-term maternal and offspring health consequences, a process that may contribute to the larger racial health disparity.