Cytoskeletal Mechanical Transduction of Force in Platelets Attaching in Flow

血小板是一种血细胞，在受伤后通过与血液和身体的其他部分形成粘连来帮助止血。他们必须能够分辨出出血和在健康血管上翻滚和碰撞时遇到的普通力量之间的区别。这一点很重要，这样血小板就不会在健康的血管中自发形成血栓而导致中风。控制凝血的生化信号已被深入研究，但血小板对机械负荷的反应在很大程度上是未知的。这项研究将测试力感应在血小板参与凝血的“决定”中是否重要。该项目将确定触发血小板反应的机械线索和细胞内交流反应的内部信号。本科生和研究生生物医学工程师将进行研究。对K-12学生的互动演示将改善低年级学生参与科学教育的环境。这项研究将通过发现开发闭塞性血栓形成（中风）和一些出血性疾病的新疗法所需的基础知识而造福社会。虽然有核细胞中的机械传感和机械转导（机械信号向生化信号的转化）过程开始被理解，但机械转导在调节无核血小板粘附功能以响应其血流动力学环境中的作用和存在却知之甚少。通过研究血小板肌动球蛋白细胞骨架，本研究将利用专门的微流体装置、高速显微镜、单细胞力测量和纳米级流量量化，研究在不同的血流动力学环境下，支持牢固的整合素依赖性血小板粘附和形状变化的机械化学步骤。我们的目标是确定血小板血流动力学力与触发配体依赖性整合素聚集、肌动蛋白基细胞骨架复合物组装和细胞骨架重组的外-内信号传导过程相关。与肌球蛋白II相关的动态收缩模式将被评估，以确定导致牢固粘连和细胞脱离的血流动力学信号。最后，将定义这些处理过程中涉及的生化和生物力学信号。这项工作将提高我们对血小板在初始栓系/粘连后对血流变化的反应的理解，这是导致正常止血的基本过程，相对于出血或血栓形成。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Platelets are blood cells that help to stop bleeding after injury by forming adhesive bonds to other parts of the blood and body. They must be able to tell the difference between bleeding and the ordinary forces encountered as they tumble and bump along a healthy blood vessel. This is important so that platelets don't cause a stroke by spontaneously forming blood clots in healthy vessels. The biochemical signals governing clotting have been intensely studied, but the response of platelets to mechanical loading is largely unknown. This research will test whether force sensing is important in the 'decision' of a platelet to participate in clotting. The project will identify mechanical cues that trigger platelet responses and the internal signals that communicate the responses inside the cell. Undergraduate and graduate biomedical engineers will perform the research. Interactive demonstrations to K-12 students will improve the environment for younger students to participate in science education. This research will benefit society by discovering fundamental knowledge needed to develop new therapies for occlusive thrombosis (stroke) and for some bleeding disorders.While mechanical sensing and mechanotransduction (conversion of mechanical to biochemical signals) processes in nucleated cells are beginning to be understood, little is known about the role and existence of mechanotransduction in regulating anucleate platelet adhesive functions in response to their hemodynamic environment. By investigating the platelet actomyosin cytoskeleton, efforts of this work will aim to examine the mechanochemical steps that support firm integrin-dependent platelet adhesion and shape change under varied hemodynamic environments using specialized microfluidic devices, high speed microscopy, single cell force measurements, and nanoscale flow quantification. We aim to define the platelet hemodynamic forces relative to outside-in-signaling processes that trigger ligand-dependent integrin clustering, assembly of actin-based cytoskeletal complexes, and cytoskeletal reorganization. Dynamic contractile patterns associated with myosin II will be assessed to identify hemodynamic signals that lead to firm adhesion and cell detachment. Lastly, biochemical and biomechanical signals involved in these processed will be defined. This work will improve our understanding of how platelets respond to changes in flow after their initial tethering/adhesion, which is fundamental to processes that lead to normal hemostasis, relative to bleeding or thrombosis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.