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PROJECT 3: PROJECT SUMMARY
Anemia is a common medical condition in preterm infants. Previous studies generated from this Program
Project Grant (PPG) show that neurodevelopmental outcomes of preterm infants are dependent in part on the
degree of anemia. In a developmentally appropriately-timed neonatal mouse model, phlebotomy induced
anemia (PIA) of the degree commonly seen in hospitalized preterm infants results in significant short-term
dysfunction and long-term injury to multiple brain areas including the hippocampus, prefrontal cortex, striatum
and cerebellum. Potential therapies for PIA include erythropoietin (rHuEPO) administration and red blood cell
transfusion (RBCTX). Each therapy has the potential advantage to relieve tissue hypoxia induced by anemia,
but also expose the rapidly developing premature neonatal brain to potential neuropathologic processes.
Treatment with rHuEPO may be neuroprotective or alternatively, shunt limited neonatal iron reserves into
RBCs and thus restrict iron delivery, leading to worsening brain iron deficiency (ID). Animal models of neonatal
anemia due to ID demonstrate particularly profound effects on the developing brain, including its genome,
metabolome, structure, intracellular signaling pathways, electrophysiology and behavioral output. RBCTX,
while alleviating tissue hypoxia due to anemia, places the brain at risk for iron overload, inflammation and
suppression of endogenous EPO production – a potential neuronal growth factor. The overall research aim of
Project 3 is to evaluate whether rHuEPO treatment or RBCTX to relieve PIA in the newborn mouse pup
between postnatal days (P) P3 and P13 improves regional brain development and function in the neonatal
period and in young adulthood following resolution of anemia. This will be done by assessing the behavioral
function, neurometabolome, and gene and protein expression in 4 brain regions in the neonatal and adult
mouse that we have demonstrated in the previous 5 years are compromised by PIA. Aim 1 tests whether
treatment of PIA with rHuEPO beginning either prior to the onset of anemia or once anemia is present rescues
the developing brain from the adverse effects of untreated PIA. Aim 2 tests whether treatment of PIA with
RBCTX initiated at the two hematocrit thresholds comparable to those utilized in Project 4 results improves
neurodevelopmental outcome in the mouse. A multi-tiered developmental neuroscience approach that spans
gene expression to behavior is necessary provide the needed mechanistic understanding for the anticipated
results in the clinical studies proposed in Projects 1 and 4 of the PPG and to provide data to Core B to model
effects of PIA and its treatments on neurodevelopment.
Status | Finished |
---|---|
Effective start/end date | 7/1/18 → 6/30/23 |
Funding
- National Heart, Lung, and Blood Institute: $365,931.00
- National Heart, Lung, and Blood Institute: $365,930.00
- National Heart, Lung, and Blood Institute: $377,248.00
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Projects
- 1 Finished
-
Immunologic and Neurodevelopmental Consequences of Neonatal Anemia and Thrombocytopenia and their Treatments
Sola-visner, M. C., Georgieff, M. K., Feldman, H. A., Josephson, C. D., Nopoulos, P. C., Mock, D. M., Richman, L. C., Strauss, R. R. G., Strause, R. G., Veng-Pedersen, P., Widness, J. A., Ziegler, E. E., Bell, E. F. & Strauss, R. G.
National Heart, Lung, and Blood Institute
7/1/92 → 6/30/23
Project: Research project