Our lab’s research goals have been to investigate the developmental and nutritional regulation of red blood cells production. This research is important because anemia complicates the clinical care of nearly 30,000 premature neonates in US yearly and effective strategies for combating anemia must be developed. Ill premature neonates develop severe anemia, requiring multiple red blood cell transfusions. Erythropoietin, the primary endocrine hormone stimulating red blood cell production, is deficient in premature neonates. The drug, erythropoietin, although effective in adult patients, is less so in premature neonates. Our research seeks to determine why erythropoietin therapy is so ineffective in premature infants. Our research approach is two-pronged. First, we are investigating the interactions of iron and erythropoietin in at-risk neonatal and infant erythropoiesis. Delivery of sufficient iron is critical to red blood cell production. Unlike other patient populations, in early infancy, no marker of poor iron delivery exists and we are examining several options. Second, we are investigating the non-traditional roles of erythropoietin. In early development, we are exploring whether erythropoietin’s erythropoietic role is relatively less important than its other roles. Because erythropoietin exerts local effects, we are examining the effects of erythropoietin in other tissues (e.g. intestine and brain).
A. To evaluate the interactions between iron and erythropoietin in erythropoiesis. Our early work compared normal plasma erythropoietin levels and indicators of iron status in infants. Additional work showed that excessive cellular iron limits erythropoiesis by inhibiting erythropoietin production in vitro and in vivo (Kling, et al. Br J Haematol 1996 & Al Uzri, et al. 2003). In our newborn rat model of impaired tissue iron delivery, we observed that iron delivery for erythropoiesis was prioritized higher than other key tissues, disrupting normal kidney development (Drake, et al, 2009). We are currently examining placental-fetal iron trafficking in intrauterine growth retarded sheep, because fetal growth retardation impairs tissue iron delivery by shifting to red cells. Because of this fine line between sufficiency and excess, accurate indices of iron status in premature infants were needed. The zinc protoporphyrin/heme ratio (ZnPP/H), a measure of incomplete iron incorporation into henoglobin shows promise (Winzerling & Kling, 2001). We found that ZnPP/H reflects iron status in human cord blood, in large babies born to mothers with diabetes, growth retarded babies, in premature infants at hospital discharge and in newborn rats (Winzerling & Kling, 2001; Dubuque, et al. 2002; Lott, et al., 2005; Lesser, et al. 2006), but was normal in normal in normal large babies (Kleven, et al. 2006). Because of a need for early identification of impaired iron delivery in newborns, our lab also developed a technique for improving the sensitivity of ZnPP/H (Blohowiak, et al., 2008). Because we found higher levels of ZnPP/H in minority neonates, compared to Caucasian neonates, (Baumann-Blackmore, et al. 2008) we are currently determining if ZnPP/H could be used in a more general sense to screen newborns at birth in the Iron Deficiency Anemia in infancy (IDA Study). We are studying whether delayed clamping of the umbilical cord will also improve iron status in children in the IDA study.
B. To investigate non-traditional roles of erythropoietin. A reason why the drug, erythropoietin, is ineffective at preventing transfusions in premature infants is that erythropoietin’s role in producing red cell is relatively less important than in other tissues. Because milk is a source of biologically important erythropoietin, we found that erythropoietin present in mammalian milk is protected from GI degradation and is absorbed enterally (Kling, Pediatr Res 1999; Miller-Gilbert, 2001). Feeding erythropoietin increases instestinal growth in suckling rats (Kling, 2008). One potential reason why erythropoietin is ineffective in preventing transfusions is that erythropoietin’s developmental erythropoietic effects may require interacting with another hematopoietic milk borne growth factor, such as insulin-like growth factor-1 (IGF-1). We found that milk borne IGF-1 stimulated erythropoiesis, not by directly increasing erythropoietin production, but improving iron absorption (Kling, 2006), improving the effect of erythropopoietin. We are studying whether enteral erythropoietin also increases iron absorption in the intestine. Erythropoietin may also improve brain growth and protect the brain from damage and we are studying this interesting effect.