Programmatic role of maternal preconception stress on offspring metabolic health

项目总结

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.