Cytoskeletal Mechanical Transduction of Force in Platelets Attaching in Flow

流动中附着的血小板中力的细胞骨架机械传导

• 批准号: 2104093
• 负责人: David Bark
• 金额: $ 40.8万
• 依托单位: Washington University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2104093&HistoricalAwards=false
• 关键词: Cytoskeletal; Mechanical; Transduction; Force; Platelets

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.

血小板是一种血细胞，通过与血液和身体的其他部位形成粘性结合，帮助受伤后止血。他们必须能够区分出血和他们沿着健康的血管翻滚和碰撞时遇到的普通力量之间的区别。这一点很重要，这样血小板就不会通过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经得到了深入的研究，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觉在血小板参与凝血的“决定”中是否重要。该项目将识别触发血小板反应的机械信号，以及在细胞内传达反应的内部信号。本科生和研究生生物医学工程师将进行这项研究。面向K-12学生的互动演示将为更年轻的学生参与科学教育提供更好的环境。这项研究将通过发现开发治疗闭塞性血栓形成(中风)和一些出血性疾病的新疗法所需的基础知识来造福社会。虽然有核细胞中的机械传感和机械转导(机械信号到生化信号的转换)过程已开始被了解，但对于机械转导在调节无核血小板黏附功能以响应其血流动力学环境方面的作用和存在，人们知之甚少。通过对血小板肌动球蛋白细胞骨架的研究，这项工作的目的将是利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动定量来检验在不同血流动力学环境下支持牢固的整合素依赖的血小板黏附和形状变化的机械力化学步骤。我们的目标是定义与触发配体依赖的整合素聚集、基于肌动蛋白的细胞骨架复合体的组装和细胞骨架重组的外向内信号过程相关的血小板血流动力。将评估与肌球蛋白II相关的动态收缩模式，以确定导致牢固粘连和细胞分离的血流动力学信号。最后，对这些处理过程中涉及的生化和生物力学信号进行了定义。这项工作将提高我们对血小板在最初的捆绑/粘连后对血流变化的反应的理解，这是导致正常止血的过程的基础，相对于出血或血栓。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。