Understanding how perinatal inflammation directs trained immunity in offspring
Active Project Grant Awarded Last action
- Award ID
- R56AI192497
- Recipient
-
The University Of Iowa UEI Z1H9VJS8NG16
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $999,998
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 82% complete
- Originally
- Place of performance
- Iowa City, IA 52242, USA
Award details come from USAspending.gov.
Description
- Abstract
- Nearly 11% of all pregnancies result in a preterm delivery. Prematurity is the leading cause of infant death and disability, making IT a global health priority. The majority of preterm deliveries are due to chorioamnionitis, which involves infection and/or inflammation of the amnion, chorion and placenta. Chorioamnionitis is characterized by acute perinatal inflammation, and results in the fetal inflammatory response syndrome (firs). Firs is defined by elevated IL-6 in the amniotic fluid and/or umbilical cord blood. Firs is associated with an array of negative neonatal outcomes, including white matter brain injury, sepsis, necrotizing enterocolitis and death. We have shown that firs is dependent upon maternal IL-6 signaling in a murine model of sterile chorioamnionitis. We have also shown the chorioamnionitis epigenetically RE-programs human and murine neonatal monocytes and macrophages. This epigenetic RE-programming includes altered chromatin accessibility, dampened pro- inflammatory responses and improved survival during neonatal sepsis. This is consistent with trained immunity, where exposure to certain stimuli alters the epigenetic landscape of innate immune cells, allowing them to respond promptly and specifically to subsequent stimuli. Trained immunity has been well-described following exposure to the bacillus calmette-guerin vaccine or the fungal ligand b-glucan, although IT has also been reported to occur following exposure to pathogen-associated molecular patterns and cytokines. Trained immunity is generally protective against subsequent lethal infections, which is also consistent with our findings. However, a more in-depth evaluation of chorioamnionitis-induced trained immune changes is needed to improve outcomes in infants afflicted by this highly morbid condition. The central hypothesis of this proposal is that perinatal inflammation induces trained immune responses in offspring monocytes/macrophages that persist into childhood, are tissue-specific and depend on functional IL-6 signaling in both the DAM and offspring. This hypothesis will be tested with the following specific aims: 1) determine the persistence of chorioamnionitis- induced trained immune responses in offspring by assessing chromatin accessibility, histone tail modifications and cell function in human monocytes through age two and murine macrophages through adulthood, 2) determine the tissue-specificity of chorioamnionitis-induced offspring trained immune changes by assessing chromatin accessibility and function in neonatal bone marrow progenitors and the global transcriptional and chromatin accessibility landscapes at a single-cell level in neonatal lung and intestine, and 3) determine the requirement and sufficiency of IL-6 signaling in chorioamnionitis-induced offspring monocyte/macrophage trained immune changes by deleting IL-6 or IL-10 in murine dams or offspring, supplementing dams or offspring with recombinant IL-6 or exposing human neonatal monocytes to recombinant IL-6 and assessing monocyte/macrophage chromatin accessibility and function.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $499,999 | |
| Original award | $499,999 |
Quick answers
Who received award R56AI192497?
R56AI192497 was awarded to The University Of Iowa by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 22, 2025.
How much is award R56AI192497 worth?
$999,998 has been obligated on R56AI192497.
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