[R01] Circulating extracellular vesicles as functional indicators of maternal mental and physical health in pregnancy and postpartum
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2031-02-28
Importo max: 669.594 EUR
Paese: US
Descrizione
Women with high levels of adverse childhood experiences (ACEs) are at significantly greater risk for negative
health outcomes in pregnancy and postpartum, including gestational diabetes, PTB, and depressed mood.
However, we still lack biomarkers or a sufficient understanding of causal mechanisms. Extracellular vesicles
(EVs) are one of the most dynamic and abundant biological signals secreted into maternal circulation, largely
produced by the placenta – where levels increase 4-5-fold during pregnancy. Similarly, removal of the placenta
at delivery produces a dramatic drop in maternal EV concentration. Across species, we and others have identified
significant EV changes during pregnancy associated with homeostatic regulation, including glucose and
glucocorticoid levels, supporting key roles for EVs in maternal health. However, longitudinal studies in human
pregnancy and postpartum have not been conducted. We know little as to the mechanisms controlling EV
secretion or the roles for EVs in maternal pregnancy and postpartum health. Our decade’s long work identified
the X-linked gene, O-glycosyltransferase (OGT), in mouse and human placenta as a master gage of the maternal
milieu, where OGT regulation of annexin A1 (AA1) is key to EV cargo loading and secretion from the placenta.
We recently reported that placental OGT levels positively correlate with maternal EV concentration. How this
association may contribute toward postpartum health, including regulating maternal stress physiology and mood
in humans is not known. We hypothesize that increased ACEs, similar to stress in preclinical models, are
negatively associated with a cell’s ability to secrete EVs important to maintain homeostasis in the face of the
challenges of pregnancy and postpartum, producing an increasingly unhealthy state. Therefore, the goals of
these proposed studies in both mice and humans are as follows: 1) To identify cellular mechanisms involved in
EV secretion important to maternal health outcomes utilizing the placenta as a tool to genetically target OGT in
mice and examine maternal homeostatic control related to EV concentration and composition during pregnancy;
2) To examine the functional ability for a dynamic elevation in maternal EV concentration to improve homeostatic
regulation in pregnancy and postpartum using chemogenetic activation (DREADDs) of placenta trophoblast cells
in pregnancy, and by EV transfer by tail vein injection postpartum; and 3) To examine in women changes in
maternal EVs in a longitudinal pregnancy and postpartum study in association with maternal glucose and cortisol
changes, we will examine markers of physical (glucose challenge test), HPA stress (hair cortisol & stress-
stimulated salivary cortisol) and psychological (Hamilton Rating Scale for Depression, Perceived Stress Scale)
health across pregnancy and the postpartum period in 150 healthy women with varying degrees of exposure to
ACEs as measured using the ACE Questionnaire (ACE-Q).
Istituzione: UNIVERSITY OF COLORADO DENVER
PI: Tracy L Bale, C. Neill EPPERSON
Progetto: 1R01HD117700-01A1
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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