Cytoskeletal Mechanical Transduction of Force in Platelets Attaching in Flow

血小板是血细胞，通过与血液和身体的其他部分形成粘合剂来帮助受伤后止血。 他们必须能够区分出血和普通力量之间的区别，因为他们沿着沿着健康的血管翻滚和碰撞。 这一点很重要，这样血小板就不会在健康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是否在血小板参与凝血的“决定”中很重要。该项目将确定触发血小板反应的机械线索和传达细胞内反应的内部信号。 本科生和研究生生物医学工程师将进行研究。 互动示范K-12学生将改善环境，年轻学生参与科学教育。这项研究将通过发现开发闭塞性血栓形成（中风）和某些出血性疾病的新疗法所需的基础知识来造福社会。有核细胞中的（机械信号到生物化学信号的转换）过程开始被理解，关于机械力转导在调节无核血小板粘附功能中的作用和存在知之甚少，血流动力学环境。通过研究血小板肌动球蛋白细胞骨架，这项工作的努力将旨在研究机械化学步骤，支持公司整合素依赖性血小板粘附和形状变化下不同的血液动力学环境，使用专门的微流体设备，高速显微镜，单细胞力测量，和纳米级流量定量。 我们的目的是确定血小板血流动力学力量相对于外-内信号传导过程，触发配体依赖性整合素聚集，装配肌动蛋白为基础的细胞骨架复合物，和细胞骨架重组。将评估与肌球蛋白II相关的动态收缩模式，以确定导致牢固粘附和细胞脱离的血流动力学信号。最后，生化和生物力学信号参与这些处理将被定义。这项工作将提高我们对血小板在最初的束缚/粘附后如何应对流量变化的理解，这是导致正常止血过程的基础，相对于出血或血栓形成。该奖项反映了NSF的法定使命，并通过使用基金会的智力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.