Dissecting the molecular determinants dictating red blood cell lifespan

红细胞（rbc）是我们体内数量最多的细胞。由于红细胞不含其他细胞类型中所含的基本细胞器，过去它们被简单地称为携带氧气的“血红蛋白袋”。然而，我们现在知道它们有一种专门的细胞机制来调节它们广泛的生理功能。成熟无核红细胞在循环中的平均寿命约为100-120天。在循环过程中，红细胞不断受到各种环境的挑战。当红细胞不能对抗这些压力源时，它们就会受伤并经历代谢重编程，从而影响它们的整体稳态。同样，衰老的红细胞也会经历衰老，并表现出多种生化变化，微粒脱落，变形能力降低，这为它们的吞噬清除和脾分解代谢做好了准备。尽管它们明显相似，但循环中的红细胞群体表现出功能异质性，这决定了个体红细胞的寿命。支撑它们在循环中寿命的分子机制仍然不完全清楚。本研究计划的目的是了解一氧化氮（NO）的作用，一氧化氮是一种有效的生物介质，参与了许多细胞过程，在正常红细胞功能的调节中。使用广泛的细胞和分子生物学工具以及系统生物学方法，我的研究将通过全面绘制NO调节的蛋白质改变模式来检查红细胞和红细胞衍生微粒中的不同信号网络。我的研究将进一步探索潜在的no介导的机制，影响小鼠在高海拔地区暴露于缺氧条件下的红细胞功能。最后，我将研究血管内皮细胞在循环中受伤时通过吞噬红细胞而影响红细胞寿命的分子机制。从这个研究项目中获得的基础科学知识将提高我们对RBC如何在不同环境挑战下茁壮成长和适应的理解。这些研究的结果可能在改善血库和输血结果中的红细胞产品质量，改善运动员和高海拔地区人群的组织氧合和表现，以及对抗全身性疾病中的红细胞功能障碍和贫血的治疗手段方面具有未来的应用价值。参与本研究的学员将获得经验，知识和技能，为确定参与调节红细胞寿命和功能的分子靶点的新策略做出贡献。这种自然科学知识的翻译将有利于改善加拿大人的健康和生活质量。

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.