The overall goal of this project is to improve the efficacy of transfusion of stored blood. There is good evidence that red blood cell storage results in loss of functionality and integrity of red blood cells over time and that this contributes to deleterious effects upon blood transfusion. This project is built around the hypothesis that this storage lesion is largely due to dysregulation of nitric oxide homeostasis in the blood. This disruption is due to increased nitric oxide scavenging by cell-free hemoglobin and microparticles that are released during hemolysis in stored blood and diminished nitric oxide production by the newly discovered red cell nitric oxide synthase. A vast array of clinical, biophysical, molecular biology, and biochemical tools will be applied to characterize the nitric oxide storage lesion in vitro in stored blood as well as in chimeric mice models, a canine model, and in human studies. In addition, therapeutics will be explored in these systems that could restore nitric oxide homeostasis by reducing nitric oxide scavenging and increasing nitric oxide production.
(provided by applicant): There are several potential risks associated with transfusion of stored red blood cells, a procedure performed about 14 million times per year in patients undergoing surgery or with chronic illness. This project explores the hypothesis that deleterious effects of red cell transfusion are due to resulting upset in the availability of the important signaling molecule nitric oxide. The project investigates the cause of this reduction in nitric oxide bioavailability and explores ways to restore nitric oxide upon red cell transfusion.
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|Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:|
|Gladwin, Mark T (2017) Translational Advances in the Field of Pulmonary Hypertension Bench to Bedside: How Fundamental Discoveries in Science Are Advancing Our Understanding and Therapy of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:1-3|
|Kato, Gregory J; Steinberg, Martin H; Gladwin, Mark T (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127:750-760|
|Suffredini, Dante A; Xu, Wanying; Sun, Junfeng et al. (2017) Parenteral irons versus transfused red blood cells for treatment of anemia during canine experimental bacterial pneumonia. Transfusion 57:2338-2347|
|Kanias, Tamir; Lanteri, Marion C; Page, Grier P et al. (2017) Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study. Blood Adv 1:1132-1141|
|Amdahl, Matthew B; Sparacino-Watkins, Courtney E; Corti, Paola et al. (2017) Efficient Reduction of Vertebrate Cytoglobins by the Cytochrome b5/Cytochrome b5 Reductase/NADH System. Biochemistry 56:3993-4004|
|Amdahl, Matthew B; DeMartino, Anthony W; Tejero, Jesús et al. (2017) Cytoglobin at the Crossroads of Vascular Remodeling. Arterioscler Thromb Vasc Biol 37:1803-1805|
|Koch, Carl D; Gladwin, Mark T; Freeman, Bruce A et al. (2017) Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med 105:48-67|
|Lee, Janet S; Kim-Shapiro, Daniel B (2017) Stored blood: how old is too old? J Clin Invest 127:100-102|
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