This program seeks to determine the mechanisms responsible for toxicities associated with acellular hemoglobins (Hbs) in blood and to establish strategies to prevent or reverse these toxicities. The results will have a significant impact on hematology and transfusion medicine by: (1) providing rational therapies to minimize the clinical problems associated with Hb released from autologous, hemolyzed red blood cells in patients with chronic or acute diseases and from heterologous stored blood used for transfusions and (2) Identifying the underlying causes of the commercial failure of extracellular Hb-based oxygen carriers (HBOCs), providing strategies to mitigate or eliminate these problems, and optimizing their efficacy for volume expansion and tissue perfusion with reduced toxicity. A long term goal is to provide safer and more effective blood transfusions using therapeutic options that match transfusion strategies with clinical needs and availability of fresh stored blood. These objectives will be achieved through 3 projects, and 4 core facilities. Project 1 (UCSD, M. Intaglietta, PI) wil use microvascular perfusion markers to identity Hb-related changes in capillary function and examine Hb toxicity during acute and chronic vascular dysfunction. Project 2 (Rice U., J. Olson, PI and A. Alayash, FDA) will engineer recombinant Hb with varied (high/low) 02 binding, NO dioxygenation, oxidation, and denaturation properties and use them to test the importance of NO scavenging, oxidative degradation, denaturation and precipitation, and impaired clearance in causing plasma Hb toxicity in cellular, organ, and whole animal model systems. Project 3 (AECOM, J. Friedman, PI) will evaluate whether PEGylation or polymerization of Hb, generation of bioactive NO by Hb, injection of nanoparticles releasing NO or GSNO, and the infusion of reducing agents and haptoglobin can be used effectively to limit toxicity derived from the oxidative reactions of acellular Hb. The four Cores are: Core A, Administrative unit (AECOM, Friedman, PI);Core B, HbA Chemical Modifications and Nanoparticle Production (AECOM, Nacharaju, leader);Core C, Recombinant HbA Production for In Vivo Toxicity Studies (Rice U. Olson, leader);Core D, Chemical, Cellular, And Animal Toxicity Evaluations (FDA, Alayash leader)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Mitchell, Phyllis
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Albert Einstein College of Medicine
Schools of Medicine
United States
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Meng, Fantao; Tsai, Amy G; Intaglietta, Marcos et al. (2015) PEGylation of ??-Hb using succinimidyl propionic acid PEG 5K: Conjugation chemistry and PEG shell structure dictate respectively the oxygen affinity and resuscitation fluid like properties of PEG ??-Hbs. Artif Cells Nanomed Biotechnol 43:270-81
Yalcin, Ozlem; Ortiz, Daniel; Tsai, Amy G et al. (2014) Microhemodynamic aberrations created by transfusion of stored blood. Transfusion 54:1015-27
Alayash, Abdu I (2014) Blood substitutes: why haven't we been more successful? Trends Biotechnol 32:177-85
Belcher, John D; Chen, Chunsheng; Nguyen, Julia et al. (2014) Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123:377-90
Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen et al. (2014) Localized increase of tissue oxygen tension by magnetic targeted drug delivery. Nanotechnology 25:265102
Chatpun, Surapong; Cabrales, Pedro (2014) Nitric oxide synthase inhibition attenuates cardiac response to hemodilution with viscogenic plasma expander. Korean Circ J 44:105-12
Ortiz, Daniel; BriceƱo, Juan Carlos; Cabrales, Pedro (2014) Microhemodynamic parameters quantification from intravital microscopy videos. Physiol Meas 35:351-67
Mollan, Todd L; Jia, Yiping; Banerjee, Sambuddha et al. (2014) Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin. Free Radic Biol Med 69:265-77
Ortiz, Daniel; Barros, Marcelo; Yan, Su et al. (2014) Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood. Am J Emerg Med 32:248-55
Sriram, Krishna; Intaglietta, Marcos; Tartakovsky, Daniel M (2014) Non-Newtonian flow of blood in arterioles: consequences for wall shear stress measurements. Microcirculation 21:628-39

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