Modeling the effects of the GUT microbiota of undernourished mothers with environmental enteric dysfunction on vascular remodeling at the fetal-placental interface
Active Project Grant Awarded Last action
- Award ID
- F30HD115307
- Recipient
-
The Washington University UEI L6NFUM28LQM5
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $357,772
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 84% complete
- Place of performance
- St. Louis, MO 63110, USA
Award details come from USAspending.gov.
Description
- Abstract
- Maternal undernutrition affects 50% of the world's female population. Maternal weight before pregnancy is a strong predictor of intrauterine growth restriction (iugr), low birth weight, and future childhood stunting. While humanitarian efforts to improve nutritional status have focused primarily on children; there is little understanding of mechanisms underlying maternal undernutrition and its transmission to children. Our lab has identified perturbations in postnatal GUT microbiota development that are evident in feces and the small intestine (SI). Our gnotobiotic mouse models have provided preclinical evidence that the SI microbiota of bangladeshi children with stunting is causally related to the pathogenesis of a poorly understood enteropathy [environmental enteric dysfunction (EED)] characterized by loss of SI villi, reduction in intestinal absorptive area, epithelial barrier dysfunction and associated intestinal and systemic inflammation. The goal my project is to determine the impact of the SI microbiota of women with and without EED on arterial-remodeling at the maternal-fetal interface and maternal immune responses to inflammation at the maternal-fetal interface. Tissue-resident, non-cytotoxic uterine natural killer (UNK) cells produce IFN- to remodel uterine spiral arteries into large luminal decidual arteries that maximize blood flow and nutrient delivery to the fetus. I hypothesize that maternal EED-associated SI microbiota leads to dysregulated vascular remodeling by impairing UNK cell function; this in turn reduces fetal growth by limiting nutrient availability. To test this hypothesis, aim 1 will use germ-free (GF), conventionally-raised (conv-r), and conventionalized mice (conv-d = GF mice gavaged with conv-r cecal contents) to first characterize the effects of the GUT microbiota on placental/fetal development, including placental/decidual histological structures, NK cell composition at early (E11.5) and late (E17.5) stages of pregnancy. Bulk RNA-SEQ, single-nucleus RNA-SEQ, flow cytometry, multiplex assays of tissue/serum proteins, and histo/immunohistochemical methods will be used to define the cellular transcriptional/signaling/metabolic profiles of their placenta, decidua, and intestines. The resulting datasets will be analyzed using a suite of computational tools that i have applied to a substantial amount of preliminary results. Aim 2 will use groups of gnotobiotic mice colonized with i) a consortium of cultured SI bacteria from undernourished (low-BMI) bangladeshi women with EED (based on histopathology of their duodenal mucosa obtained by endoscopy) and II) a consortium of cultured SI bacteria from healthy (normal BMI) bangladeshi women without histologic evidence of EED. I will apply methods from aim 1 to E11.5 and E17.5 mice representing the 2 treatments groups to characterize placental/fetal development (transcriptional, signaling, metabolic and immunologic characteristics of placenta, decidua, and intestines including spiral artery development and NK cell biology). These experiments should advance knowledge about how the SI microbiota in EED impacts the maternal-fetal interface and could yield new therapeutic concepts/targets.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $54,538 | |
| Amendment | $54,538 | |
| Amendment | $564 | |
| Amendment | $53,974 | |
| Amendment | $53,974 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $34,262 | |
| Amendment | $0 | |
| Amendment | $34,262 | |
| Amendment | $34,262 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $34,262 |
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Quick answers
Who received award F30HD115307?
F30HD115307 was awarded to The Washington University by National Institute of Child Health and Human Development (National Institutes of Health) on August 26, 2024.
How much is award F30HD115307 worth?
$357,772 has been obligated on F30HD115307.
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