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Attenuating the Oxidative and Myocardial Side-Effects of Acellular Hemoglobin

减轻无细胞血红蛋白的氧化和心肌副作用

基本信息

批准号：
9766406
负责人：
Pedro Cabrales
金额：
$ 37.15万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766406
关键词：
Affinity Animal Model Animals Antioxidants Attenuated Biotechnology Blood Preservation Blood Vessels Blood Volume Cardiac Carrying Capacities Cattle Cavia Cells Chemistry Cholesterol Clinical Clinical Trials Deposition Development Diffusion Emerging Communicable Diseases Endothelial Cells Endothelium Erythrocytes Event Experimental Animal Model Extravasation Formulation Glutaral Heme Hemoglobin Hemorrhage Hemorrhagic Shock Human Hyperbaric Oxygenation Hypertension Incidence Infusion procedures Injury Intercellular Junctions Iron Laboratories Lead Light Lipids Methemoglobin Myocardial Myocardial Infarction Nitric Oxide Nucleic Acids Organ Oxidation-Reduction Oxidative Stress Oxides Oxygen Perfusion Permeability Phase III Clinical Trials Physiological Polymers Population Prevention Prosthesis Proteins Regulation Resuscitation Risk Role Safety Signal Transduction Smooth Muscle Myocytes Systemic hypertension Testing Tissues Toxic effect Transfusion Translating Vascular blood supply Vascular resistance Work base biophysical techniques crosslink endothelial dysfunction heart function heart preservation hemodynamics hemoglobin polymer improved innovation molecular carrier molecular size novel oxidation oxidative damage prevent public health relevance response screening side effect transfusion medicine vasoconstriction

项目摘要

DESCRIPTION: Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are currently being developed as red blood cell (RBC) substitutes for use in transfusion medicine. Despite significant commercial development, recent late stage clinical results of polymerized hemoglobin (PolyHb) solutions (i.e. Hemopure (OPK Biotech, Cambridge, MA), a glutaraldehyde polymerized bovine Hb; and PolyHeme (Northfield Laboratories Inc., Evanston, IL), a glutaraldehyde polymerized pyridoxylated human Hb) hamper further development. Both of these commercial products elicit vasoconstriction at the microcirculatory level, and lead to the development of systemic hypertension and oxidative tissue damage. These side-effects are hypothesized to occur either by a nitric oxide (NO) scavenging or oxygen (O2) oversupply mechanism and are both exacerbated by PolyHb extravasation into the tissue space. In light of these 2 potential mechanisms, it is apparent that PolyHb size will have a profound impact on the extent of vasoconstriction, systemic hypertension and oxidative tissue toxicity. Therefore in this application, we hypothesize that PolyHb size will regulate vasoconstriction at the microcirculatory level, systemic hypertension and tissue oxidative damage. In order to test this hypothesis, we plan to synthesize several PolyHbs of varying size in the low O2 affinity state by cross-linking/polymerizing bovine Hb using the cross-linking agent glutaraldehyde. In order to test the central hypothesis of this application, we propose 3 specific aims: Specific Aim 1: Analyze the role of endothelial function on the development of oxidative tissue injury to PolyHbs of varying size. Specific Aim 2: Analyze cardiac function in the presence of PolyHbs of varying size. Specific Aim 3: Evaluate the ability of PolyHb to restore perfusion and oxygenation after resuscitation from hemorrhagic shock. The proposed work is both significant and innovative, since it seeks to develop safe and efficacious PolyHbs for use in transfusion medicine. In addition, state-of-the-art biophysical techniques and two unique animal models will be used to understand PolyHb physiological responses and determine the clinical potential of these novel materials.