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
Kettisen, Karin; Strader, Michael Brad; Wood, Francine et al. (2018) Site-directed mutagenesis of cysteine residues alters oxidative stability of fetal hemoglobin. Redox Biol 19:218-225
Alayash, Abdu I (2018) Oxidative pathways in the sickle cell and beyond. Blood Cells Mol Dis 70:78-86
Wallace, Martina; Green, Courtney R; Roberts, Lindsay S et al. (2018) Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat Chem Biol 14:1021-1031
Sjodt, Megan; Macdonald, Ramsay; Marshall, Joanna D et al. (2018) Energetics underlying hemin extraction from human hemoglobin by Staphylococcus aureus. J Biol Chem 293:6942-6957
Jana, Sirsendu; Strader, Michael Brad; Meng, Fantao et al. (2018) Hemoglobin oxidation-dependent reactions promote interactions with band 3 and oxidative changes in sickle cell-derived microparticles. JCI Insight 3:
Kassa, Tigist; Strader, M B; Nakagawa, Akito et al. (2017) Targeting ?Cys93 in hemoglobin S with an antisickling agent possessing dual allosteric and antioxidant effects. Metallomics 9:1260-1270
Martucci, Alexandre Fabricio; Abreu Martucci, Ana Carolina Carvalho Ferreira; Cabrales, Pedro et al. (2017) Acute kidney function and morphology following topload administration of recombinant hemoglobin solution. Artif Cells Nanomed Biotechnol 45:24-30
Jana, Sirsendu; Meng, Fantao; Hirsch, Rhoda E et al. (2017) Oxidized Mutant Human Hemoglobins S and E Induce Oxidative Stress and Bioenergetic Dysfunction in Human Pulmonary Endothelial Cells. Front Physiol 8:1082
Cardenas, Andres S Benitez; Samuel, Premila P; Olson, John S (2017) 2017 Military Supplement: Current Challenges in the Development of Acellular Hemoglobin Oxygen Carriers by Protein Engineering. Shock :
Ao-Ieong, Eilleen S Y; Williams, Alexander; Jani, Vivek et al. (2017) Cardiac function during resuscitation from hemorrhagic shock with polymerized bovine hemoglobin-based oxygen therapeutic. Artif Cells Nanomed Biotechnol 45:686-693

Showing the most recent 10 out of 105 publications