RBC transfusion exacerbates brain inflammation in anemic murine neonates and causes long term neurodevelopment impairment
Active Project Grant Awarded Last action
- Award ID
- R01HD116950
- Recipient
-
The University Of Texas Southwestern Medical Center UEI YZJ6DKPM4W63 Part of Board Of Regents Of University Of Nebraska
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,378,558
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 37% complete
- Place of performance
- Dallas, TX 75390, USA
Award details come from USAspending.gov.
Description
- Abstract
- Red blood cell transfusions (rbct) are necessary and life-saving in premature and critically ILL infants, who experience severe anemia due to both physiologic and iatrogenic factors. Recently, we have elucidated the connection between anemia and necrotizing enterocolitis (NEC); specifically, the "leaky GUT" presentation characterized by monocytic infiltration, RBC transfusion-associated activation of infiltrated monocytes, and the resulting intestinal mucosal injury. Neurocognitive development is often impaired in patients with NEC and, a large clinical trial confirmed that RBC transfusion in extremely premature infants may contribute to these neurodevelopmental outcomes. This finding is supported by several preclinical studies. However, the underlying mechanism(s) by which anemia and RBC transfusion directly or indirectly correlate with neurocognitive impairment through the development of an inflammatory cascade is unclear. Critical evaluation of the association between anemia/RBC transfusion and anemia-transfusion-associated brain inflammation (atbi) and their effects on neurodevelopment are necessary to improve clinical practice and develop therapeutic strategies for prevention or amelioration. Our preliminary studies using our established pre-clinical murine model of anemia/RBC transfusion demonstrate that anemia is associated with a "leaky GUT" that leads to endotoxin in the bloodstream, causing early brain inflammation by activation of microglia. Then, RBC transfusion potentiates this early brain inflammation by recruitment of NEC-causing monocytes (raised from the intestine) in the brain. Consistent with this finding, the brain inflammatory response could be dampened either by depletion or inhibition of NEC-causing monocytes. Thus, here we will propose a novel hypothesis that anemic neonates are uniquely predisposed to early brain inflammation, and rbct exacerbates this brain inflammation leading to altered neurodevelopment. We propose this finding in anemic premature infants due to infiltration of inflammatory activated monocytes, with a phenotype similar to monocytes found in the anemic-RBC transfused intestine via the 'GUT-brain axis'. To test our central hypothesis, we will pursue the following specific aims: aim 1: elucidate the mechanisms by which severe anemia and rbct induce/exacerbate monocyte infiltration and cause inflammation in the neonatal brain. Aim 2: investigate the role of rbct-NEC causing monocytes in atbi. Aim 3: determine the effect of phlebotomy-induced anemia and neonatal atbi on neurocognitive impairment in adulthood. Our studies will have therapeutic implications for treating anemia/RBC transfusion-associated brain inflammation, as the elimination of the NEC-causing inflammatory monocytes could contribute to the amelioration of neurodevelopment deficits.
Transactions
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| Amendment | $415,832 | |
| Amendment | $415,832 | |
| Amendment | $415,832 | |
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| Original award | $415,832 |
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Quick answers
Who received award R01HD116950?
R01HD116950 was awarded to The University Of Texas Southwestern Medical Center by National Institute of Child Health and Human Development (National Institutes of Health) on December 18, 2024.
How much is award R01HD116950 worth?
$3,378,558 has been obligated on R01HD116950.
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