CAREER: Biomechanics of Red Blood Cell Adhesion and Deformability

健康的红细胞是柔软的，没有粘性，所以它们可以很容易地穿过体内最狭窄的血管。红细胞硬度和黏性的增加会损害血液循环，这确实发生在许多疾病和病症中，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、肥胖和一些神经系统疾病。在这些情况下，医学对红细胞的机械变化还没有完全的了解。这个教师早期职业发展（Career）项目将通过使用特殊的微通道设备来提高我们对微循环中红细胞粘附性和可变形性的认识，这种设备具有可调节的粘性，人们可以看到细胞在流动、变形和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）教育项目向社区传播。STArt计划旨在通过动手，科学艺术主题研讨会激发高中学生的科学好奇心和兴趣。本CAREER奖的研究目的是验证红细胞的粘附亲和力是其可变形性和磷脂酰丝氨酸向外膜表面易位的函数这一假设。红细胞特殊的可变形性是由其与粘附受体物理连接的膜骨架促进的。磷脂酰丝氨酸是一种位于细胞膜内小叶的磷脂。尽管磷脂酰丝氨酸向外膜表面的移位与粘附有关，但其在红细胞粘附亲和力增加中的作用尚不清楚。该研究将在单细胞水平上系统地研究微生理血流中活红细胞的生物力学特性。获得的新知识将回答以下重要问题：(1)哪一种红细胞受体与较高的粘附亲和力和较低的变形性相关？(2)粘附亲和力是红细胞变形能力、磷脂酰丝氨酸易位和功能的替代指标吗？(3)仅凭粘附亲和力和变形性降低，就能识别出不健康的红细胞并将其排除在循环之外吗？拟议的研究将开拓对红细胞粘附性和变形性的综合理解，这可能与任何伴有微循环损伤的疾病有关。

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.