Acellular Hb in the circulation has been proposed to be a major source of toxicity and poor outcome for transfusions involving either aged RBCs or HBOCs. One of the major overall objectives of this program project is to test the hypothesis that acellular Hbs contribute to these poor outcomes due to depletion of endothelium-generated NO and that acellular Hb toxicity can be reversed through compensatory mechanisms that generate bioactive NO. Project 3 in conjunction with the other projects will: i) determine the role of bioactive NO in the creation or exacerbation of acellular Hb induced toxicities; and ii) establish of the role of released or nitrite-generated bioactive NO in preventing, limiting, or ameliorating acellular Hb toxicities. Project 3 will contribute to these objectives through the following three Specific Aims: i) Test the hypothesis that a combination of an appropriately modified Hb and added cofactors can produce a formulation that is highly effective in generating long lived forms of bioactive NO;ii) Test the hypothesis that a new biocompatible NO-releasing nanoparticle platform with proven in vivo efficacy as a vasodilator can be further modified to provide for sustained production of both NO and nitrosothiols at therapeutically effective levels suitable for transfusion medicine;and iii) Test the hypothesis that effective generation of bioactive NO from either Hb or nanoparticles can be used to limit or reverse specific oxidative reactions of Hb such as ferryl and tyrosine radical formation that have been implicated in mechanisms of acellular Hb toxicity (Project 2, Core D).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL110900-03
Application #
8707843
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$290,549
Indirect Cost
$49,419
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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