Dissecting the molecular determinants dictating red blood cell lifespan

红细胞（RBC）是我们身体中数量最多的细胞。由于红细胞不包含在其他细胞类型中发现的基本细胞器，在过去，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特殊的细胞机制，可以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。在循环中，RBC不断暴露于各种环境挑战。当红细胞无法抵抗这些压力时，它们就会受伤并经历代谢重编程，这会影响它们的整体稳态。类似地，老化的RBC经历衰老并显示出多种生化变化、微粒脱落和降低的变形性，这使它们准备进行吞噬清除和脾细胞增殖。尽管它们具有明显的相似性，但循环中的RBC群体表现出功能异质性，这决定了单个RBC的寿命。维持它们在循环中寿命的分子机制仍然不完全清楚。这项研究的目的是了解一氧化氮（NO），一个有效的生物介质参与了主机的细胞过程，在正常的红细胞功能的调节作用。使用广泛的细胞和分子生物学工具，和系统生物学方法，我的研究将通过全面绘制由NO调节的蛋白质改变的模式来检查RBC和RBC衍生微粒中的不同信号传导网络。我的研究将进一步探索潜在的NO介导的机制，这些机制影响暴露于高海拔缺氧条件下的小鼠RBC功能。最后，我将调查的分子机制，内皮细胞内衬的血管，可以影响红细胞的寿命吞噬他们时，受伤的循环。从这项研究计划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RBC产品质量，改善运动员和居住在高海拔地区的运动员的组织氧合和性能，以及对抗系统性疾病中RBC功能障碍和贫血的治疗方法方面具有未来的应用。参与这项研究的学员将获得经验，知识和技能，以有助于确定参与调节RBC寿命和功能的分子靶点的新策略。这些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.