Dissecting the molecular determinants dictating red blood cell lifespan

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Red blood cells (RBCs) are the most numerous cells in our body. As RBCs do not contain essential organelles found in other cell types, in the past they were simply known as "bags of hemoglobin" carrying oxygen. However, we now know that they have a specialized cellular machinery which regulates a wide range of their physiological functions. The average lifespan of mature anucleated RBCs in the circulation is approximately 100-120 days. In the circulation, RBCs are constantly exposed to a variety of environmental challenges. When RBCs fail to counter these stressors they are injured and undergo metabolic reprogramming, which impacts their overall homeostasis. Similarly, aged RBCs undergo senescence and display multiple biochemical changes, microparticle shedding, and reduced deformability, which prime them for phagoyctic clearance and splenic catabolism. Despite their apparent similarities, RBC populations in the circulation exhibit functional heterogeneity, which dictates the lifespan of individual RBCs. The molecular mechanisms underpinning their lifespan in the circulation remain incompletely understood. The aim of this research proposal is to understand the role of nitric oxide (NO), a potent biological mediator involved in a host of cellular processes, in the regulation of normal RBC functions. Using a wide array of cellular and molecular biology tools, and systems biology approaches, my research will examine different signaling networks in RBCs and RBC-derived microparticles by comprehensively mapping the pattern of protein alterations regulated by NO. My research will further explore the underlying NO-mediated mechanisms which influence RBC functions in mice exposed to hypoxic conditions encountered at higher altitudes. Finally, I will investigate the molecular mechanisms by which endothelial cells lining the blood vessels, can affect RBC lifespan by engulfing them when injured in the circulation. The basic science knowledge gained from this research program will improve our understanding of how RBC thrive and adapt under different environmental challenges. The results from these studies may have future applications in improving RBC product quality in blood banking and transfusion outcomes, improving tissue oxygenation and performance in athletes and those dwelling at higher altitudes, and therapeutic means to counter RBC dysfunction and anemia in systemic diseases. Trainees involved in this research will gain experience, knowledge, and skill sets to contribute to new strategies for identifying molecular targets involved in regulating RBC longevity and function. Translation of this natural sciences knowledge will be beneficial in improving the health and quality of life for Canadians.