Our laboratory has focused on understanding the mechanisms controlling acellular Hbs oxidative and nitrosative toxicities in vitro and in vivo. Evidence is accumulating which suggests that reduction-oxidation "redox" reactions of free Hb and hemoglobin-based oxygen carriers (HBOCs), also known as "blood substitutes" do occur in vivo with some potentially serious clinical consequences. A primary focus of the research is based on the role of oxidants-mediated changes in acellular Hb under conditions that can mimic ischemia/reperfusion injury. Depending on whether host endogenous reductive mechanisms are employed or not, we will investigate Hb oxidative reactions in vivo using rats (ascorbate producing) or guinea pigs (ascorbate non-producing). The role of haptoglobin (Hp) and/or other antioxidant materials in supplementing endogenous antioxidant mechanisms will be investigated. For the investigation of effects of oxygen carrying HBOCs on cardiac performance under hypoxia, we will perfuse isolated hearts from rats with a number of Hbs and/or antioxidant materials. Previous experiences from our laboratory make us uniquely positioned to critically evaluate Hb oxidative processes with regard to heme iron, amino acids and protein structure both in vitro and in vivo and the implementation of any successful therapeutic strategies designed collectively within this program.
Our specific aims for Core D are to: 1) Determine oxidative and nitrosative characteristics of acellular Hbs in the presence or absence of specific nanomaterials in vitro. Studies will include autoxidation rate determination, H2O2 induced heme iron oxidation, protein oxidative changes, heme degradation and nitric oxide (NO)-driven oxidation reactions as outlined in both project 2 and 3. 2) Determine redox transition of acellular Hbs in cell culture media and/or in isolated organ under normoxia and hypoxia as well as their ability to carry oxygen and whether any given candidate(s) will proceed to the next level of in vivo evaluation in an appropriate animal model. 3) Perform a 50-80% exchange transfusion of blood from guinea pigs or rats with individual acellular Hbs. HIF-1 a protein, and down stream genes such as erythropoietin (Epo), endothelial nitric oxide synthase (eNos), heme oxygenase (Ho-1) and vascular endothelial growth factor (Vegf) will be evaluated by conventional molecular biology techniques. This together with in vivo work carried out in the microcirculation in project 1, will allow us to determine what particular chemistry of a given Hb/or additive offers advantage over others in terms of oxygen carrying and redox stability of'the carrier molecule.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL110900-03
Application #
8707847
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
$242,841
Indirect Cost
$49,418
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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