Saturday, April 27, 2024
4/27/2024
PROJECT SUMMARY Parturition is a highly inflammatory event characterized by an upregulation of pro-inflammatory cytokine production, maternal leukocyte activation, and cellular infiltration into the uterus. However, untimely inflammatory triggers may shift the maternal immune system towards the transition to labor early, such as in cases of preterm birth (PTB). Currently, the mechanisms involved in the switch to a pro-inflammatory state and parturition initiation is largely unknown. Evidence supports circulating damage-associated molecular patterns (DAMPs) in the maternal blood, such as cell-free fetal DNA (cffDNA), may trigger sterile inflammation and labor through activation of maternal innate immune cells. cffDNA is continuously released from the placenta into the maternal bloodstream with concentrations steadily increasing as pregnancy progresses, becoming undetectable hours after parturition. Importantly, cffDNA is abnormally elevated in pathological pregnancies, including PTB. The Enninga lab showed cffDNA, but not cell-free DNA (cfDNA), can activate maternal monocytes through cGAS/STING to initiate hallmark processes of parturition; however, the mechanism of cffDNA activation or why it is a potent immunostimulatory molecule remains incompletely understood. This F31 proposal seeks to evaluate whether inhibiting the cGAS/STING pathway can reduce CD14+ monocyte activation and the pro-inflammatory cascade following cffDNA recognition (Aim 1) and identify the immunostimulatory properties of cffDNA specific sequence motifs (Aim 2). Completion of these studies will provide better understanding of the immunological processes driving labor at term. Additionally, it may provide a novel small molecule target that could be tested clinically for dampening systemic maternal immune activation, which would be especially important for PTB prevention. This award will provide Raini Sorenson with individualized, mentored training from excellent faculty sponsors while working on dissertation research in immunology. Furthermore, this training award will facilitate Raini’s development into a strong applicant for a competitive post-doctoral position.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
