# Project 2

> **NIH NIH P01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $384,346

## Abstract

PROJECT 2: PROJECT SUMMARY
Anemia represents one of the most common complications of preterm birth. Treatment of neonatal anemia is
largely based on measured hemoglobin concentrations (Hb). As patient blood management practices have
become more conservative, and neonatologists have utilized lower Hb thresholds to trigger transfusions,
recent studies have raised concerns regarding the health consequences of restrictive transfusion practices.
Consistent with this, our recent multicenter prospective cohort investigation demonstrated that anemia in
preterm infants (Hb ≤8g/dL) is associated with the development of necrotizing enterocolitis (NEC), a serious
intestinal disease and major cause of death in preterm neonates. Our long-term objective is to identify key
mechanisms that regulate anemia-associated gut injury and NEC. Our central hypothesis is that severe
anemia induces alterations in macrophage function that directly predisposes neonates to intestinal injury and
NEC. Our hypothesis is formulated on the basis of our recent discovery that anemia in preterm infants can
result in impaired gut oxygenation as measured by near infrared spectroscopy (NIRS) of mesenteric regional
saturation of oxygen (MES-rSO2). Anemic preterm infants can also display significant increases in serum levels
of proinflammatory interferon gamma (IFNγ). Using a preclinical model, our preliminary data also demonstrate
that severe anemia not only induces gut hypoxia, but also drives IFNγ production by intestinal macrophages.
As anemia can induce hypoxia-inducible factor 1α (HIF1α) in macrophages and HIF1α can drive macrophage-
production of IFNγ, these results suggest that anemia-induced changes in gut oxygenation drive HIF1α-
induced IFNγ production by intestinal macrophages. Furthermore, as our preliminary data demonstrate that
anemia induces intestinal injury and previous studies demonstrate that IFNγ can directly compromise epithelial
barrier function, anemia-induced production of IFNγ by macrophages may directly compromise the integrity of
the gut mucosa in addition to driving a positive feedback loop of additional proinflammatory monocyte and
macrophage differentiation, macrophage IFNγ production, barrier dysfunction, intestinal injury and ultimately
NEC. To test our central hypothesis and therefore accomplish the overall objectives of Project 2, we will
pursue the following specific aims: Aim 1: Define the impact of anemia and its treatment (RBC transfusion) on
serum cytokines and monocyte differentiation in pre-term infants. Aim 2: Define the impact of anemia and its
treatment (RBC transfusion or recombinant human erythropoietin (rHuEPO) administration) on gut
macrophage cytokine secretion and intestinal injury using a preclinical model. We think these parallel aims
provide a unique opportunity to define the impact of anemia on intestinal injury and NEC and therefore will help
inform future validation studies and trials designed to optimally manage neonatal anemia.

## Key facts

- **NIH application ID:** 10215594
- **Project number:** 5P01HL046925-24
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** CASSANDRA D JOSEPHSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,346
- **Award type:** 5
- **Project period:** 1992-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215594

## Citation

> US National Institutes of Health, RePORTER application 10215594, Project 2 (5P01HL046925-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10215594. Licensed CC0.

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