CAREER: Biomechanics of Red Blood Cell Adhesion and Deformability

健康的红细胞柔软且不粘性，因此即使是体内最窄的血管，它们也能轻易地滑过。红细胞的僵硬和粘性增加会损害血液循环，这在许多疾病和情况下都会发生，包括贫血、败血症、疟疾、狼疮、重金属中毒、输血并发症、糖尿病、癌症、肾脏和心血管疾病、肥胖和一些神经疾病。医学对红细胞在这些条件下的机械变化没有完全的了解。这一学院早期职业发展(CALEAR)项目将使用具有可调粘性的特殊制造的微通道设备来提高我们对红细胞在微循环中的粘附性和变形性的知识，在这种设备中，人们可以看到细胞在流动、变形并与微血管壁相互作用时的变形。首席研究员将利用这些实验产生的美丽图像和科学艺术，通过与克利夫兰艺术学院合作开发的科学、技术和艺术(START)教育计划，接触到社区。START计划旨在通过动手的、以科学艺术为主题的工作室激发高中生的科学好奇心和兴趣。这个职业奖项的研究目标是检验红细胞的黏附亲和力是其变形性和磷脂酰丝氨酸转移到外膜表面的函数的假设。红细胞特殊的变形性是由其膜骨架促进的，膜骨架与黏附受体物理连接。磷脂酰丝氨酸是一种位于细胞膜内叶上的磷脂。尽管磷脂酰丝氨酸移位到外膜表面与黏附有关，但它在红细胞增加黏附亲和力中的作用仍不清楚。这项研究将在单细胞水平上系统地研究活红细胞在微生理血流中的生物力学特性。所获得的新知识将回答以下重要问题：(1)哪些红细胞受体与较高的黏附亲和力和较低的变形性相关？(2)黏附亲和力是衡量红细胞变形性、磷脂酰丝氨酸转位和功能的替代指标吗？(3)仅凭黏附亲和力和降低的变形性就能识别不健康的红细胞并将其排除在循环之外吗？拟议的研究将开创对红细胞黏附和变形性的综合理解，这可能与任何伴随微循环障碍的疾病有关。

Healthy red blood cells are soft and are not sticky so that they can slip easily through even the narrowest of blood vessels in the body. Increased stiffness and stickiness of red blood cells can impair blood circulation and this does occur in many diseases and conditions, including anemias, sepsis, malaria, lupus, heavy metal poisoning, blood transfusion complications, diabetes, cancer, kidney and cardiovascular diseases, obesity, and some neurological disorders. Medicine does not have a complete understanding of the mechanical changes of red blood cells in these conditions. This Faculty Early Career Development (CAREER) project will advance our knowledge of red blood cell adhesion and deformability in the microcirculation using special built micro-channel devices that have adjustable stickiness where one can see the deformation of the cells as they flow, deform and interact with the micro-vessel walls. The principal investigator will use the beautiful imagery and the scientific art that arises from these experiments to reach out to the community through the Science, Technology and Art (STArt) education program that will be developed in collaboration with the Cleveland Institute of Art. The STArt program aims to stimulate scientific curiosity and interest in high school students through hands-on, scientific art themed workshops.The research objective of this CAREER award is to test the hypothesis that a red blood cell's adhesion affinity is a function of its deformability and phosphatidylserine translocation to the outer membrane surface. The exceptional deformability of the red blood cell is facilitated by its membrane skeleton, which is physically connected to the adhesion receptors. Phosphatidylserine is a phospholipid located on the inner leaflet of the cell membrane. Even though the translocation of phosphatidylserine to the outer membrane surface has been correlated to adhesion, its role in red blood cell's increased adhesion affinity remains unclear. The research will systematically investigate, at the single cell level, the biomechanical properties of live red blood cells in microphysiological blood flow. The new knowledge gained will answer important questions: (1) which of the red blood cell receptors are associated with higher adhesion affinity and lower deformability? (2) Is the adhesion affinity a surrogate measure of red blood cell's deformability, phosphatidylserine translocation, and function? (3) Can the unhealthy red blood cells be identified and excluded from the circulation solely based on their adhesion affinity and reduced deformability? Proposed research will pioneer an integrated understanding of red blood cell adhesion and deformability, which may be pertinent to any disease accompanied by microcirculatory impairment.