The unifying theme of this PPG renewal is understanding the pathophysiology, and establishing the optimal management, of two of the most serious and frequently encountered conditions among critically ill, premature infants: anemia and thrombocytopenia. Current treatment for these conditions relies largely on transfusion of red blood cells and platelets?therapies that remain controversial and incompletely investigated. Prior research by our PPG group and others has established that many aspects of the pathophysiology of the anemia and thrombocytopenia of prematurity are unique. However, our understanding is incomplete. Hence, the goals of our renewal are to further define the mechanisms that give rise to these pressing and related clinical conditions, to optimize their treatment per such mechanistic knowledge, and consequently, to reduce both short- and long-term disabilities associated with these conditions. Our 4 interrelated projects, whose objectives are directly relevant to our unifying theme, include: Project 1 "Optimized erythropoietin treatment of neonatal anemia," PL JA Widness (and P Veng-Pedersen);Project 2 "Pathogenesis and treatment of neonatal thrombocytopenia," PL M Sola-Visner;Project 3 "Preterm transfusions: brain structure/function outcomes," PL PC Nopoulos;and Project 4 "The role of neonatal anemia In learning and memory," PL MK Georgieff. Core A ("Administrative, statistical, and research personnel") and Core B ("Laboratory and database," PL DM Mock) will provide support for all projects. To enhance effectiveness, our program has expanded to involve four (vs. two) performance sites, so that data can be shared among Projects 1, 2 and 3 (i.e. data from the same infants will be used In studies at multiple sites). Our history of success conducting multisite research will be invaluable in coordinating studies across the various performance sites. Because our Program rests on a highly-qualified, multidisciplinary group of new and experienced investigators, our renewal program consists of unique and collaborative research teams capable of accelerating the acquisition of knowledge vital to the fields of neonatal anemia and thrombocytopenia. Over the past 17 years, our productive PPG group (200 publications) has made a substantial impact on clinical practice and research in neonatal transfusion medicine and hematology. Our program embraces and exemplifies the synergistic P01 approach, which has and will enable us to make more rapid progress than any of us could individually. With this renewal, we are poised to continue to challenge paradigms and advance knowledge, as we build on prior results and maximize collaboration.
The research proposed will enhance understanding of the pathophysiology of the 2 most important, common and costly hematological conditions encountered in the NICU: anemia and thrombocytopenia. It will do so by providing definitive answers to important, challenging, and timely clinical questions and by expanding potential treatment options to reduce costly short- and long-term consequences of these 2 challenging conditions. Results of our studies support the NIH's mission of reducing the burdens of illness and disability.
|Peters, Anna L; Beuger, Boukje; Mock, Donald M et al. (2016) Clearance of stored red blood cells is not increased compared with fresh red blood cells in a human endotoxemia model. Transfusion 56:1362-9|
|Bastian, Thomas W; Duck, Kari A; Michalopoulos, George C et al. (2016) Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost :|
|Witmer, Jordan R; Wetherell, Bailey J; Wagner, Brett A et al. (2016) Direct spectrophotometric measurement of supra-physiological levels of ascorbate in plasma. Redox Biol 8:298-304|
|Zamora, Tara G; Guiang 3rd, Sixto F; Widness, John A et al. (2016) Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs. Pediatr Res 79:922-8|
|Patel, Ravi M; Knezevic, Andrea; Shenvi, Neeta et al. (2016) Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 315:889-97|
|Patel, Ravi Mangal; Meyer, Erin K; Widness, John A (2016) Research Opportunities to Improve Neonatal Red Blood Cell Transfusion. Transfus Med Rev 30:165-73|
|Ekhaguere, Osayame A; Morriss Jr, Frank H; Bell, Edward F et al. (2016) Predictive factors and practice trends in red blood cell transfusions for very-low-birth-weight infants. Pediatr Res 79:736-41|
|Weisenhorn, Erin M M; van T Erve, Thomas J; Riley, Nicholas M et al. (2016) Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells. Mol Cell Proteomics 15:3614-3623|
|Kuruvilla, Denison J; Widness, John A; Nalbant, Demet et al. (2016) A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis. AAPS J 18:187-95|
|Al-Ghananim, Raeda T; Nalbant, Demet; Schmidt, Robert L et al. (2016) Reticulocyte Hemoglobin Content During the First Month of Life in Critically Ill Very Low Birth Weight Neonates Differs From Term Infants, Children, and Adults. J Clin Lab Anal 30:326-34|
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