Systematic multidisciplinary approach to study traumatic bleeding as a complex structural and biomechanical problem

项目摘要 纤维蛋白酶通过提供机械作用，在止血、血栓形成和伤口愈合中起关键作用。 对由于（病理）生理条件而经历变形的血凝块的稳定性。蛋白原 在创伤性损伤后迅速从血液中耗尽，这可能导致 凝血病或出血;这与死亡风险增加和 适应不良的炎症反应重要的是，创伤是死亡的主要原因， 年轻人我们已经积累了大量的证据，纤维蛋白原，纤维蛋白，和凝块结构 是血栓性疾病的关键驱动因素。然而，人们对如何改变 创伤凝血病期间纤维蛋白原和纤维蛋白凝块的形成可能与止血有关， 炎症和创伤后免疫。在具体目标1中，我建议采取多学科 一种系统地检查血凝块形成、结构、力学和纤维蛋白溶解的方法 在创伤环境中的属性。在《特定目标2》中，我计划研究纤维蛋白 和炎症细胞巨噬细胞在凝血障碍中的作用。尖端实验，成像， 和机械测试技术将用于体外和体内试验， 和患者样本，以全面了解这一复杂的过程。具体目标 3，在这次考试中获得的信息将用于通知免疫设计， 用于创伤患者的调节止血生物材料。获得基本的 这里提出的知识将有助于理解出血和止血， 纤维蛋白和炎症细胞之间的关系，以及纤维蛋白在生物材料中的应用。在指导期间， 阶段，我将获得所需的背景和实验技能，以完成拟议的 在导师团队和合作者的指导下进行研究，并为我奠定基础。 采取多学科的方法来研究这一重要和研究不足的领域。 重要的是，我的导师团队在培养博士后研究员方面有着良好的记录， 过渡到职业生涯作为一个独立的调查，并将促进不仅我的成长 研究技能，还有我的领导能力、指导能力和专业发展能力。 将K99指导阶段学到的新技能与我之前的专业知识相结合， 止血、血栓形成和凝块收缩将使我能够进行多学科的 研究血液生物材料相互作用的方法，并允许我启动一个独立的， 独特的实验室，可以影响各种领域。

Project Summary Fibrin plays a critical role in hemostasis, thrombosis and wound healing by providing mechanical stability to blood clots that undergo deformation due to (patho)-physiologic conditions. Fibrinogen is rapidly depleted from the blood following traumatic injury which can lead to the development of coagulopathy, or bleeding; this has been correlated with an increased risk of death and a maladaptive inflammatory response. Importantly, trauma is the leading cause of death among young people. We have amassed considerable evidence that fibrinogen, fibrin, and clot structure are key drivers of thrombotic disorders. However, little is known regarding how changes in fibrinogen and fibrin clot formation during trauma coagulopathy may link hemostasis, inflammation, and immunity after trauma. In Specific Aim 1 I propose to take a multidisciplinary approach to systematically examine blood clot formation, structure, mechanics, and fibrinolytic properties in the trauma setting. In Specific Aim 2 I plan to examine the interplay between fibrin and the inflammatory cells, macrophages, in coagulopathy. Cutting edge experimental, imaging, and mechanical testing techniques will be used in vitro and in vivo assays with both reconstituted and patient samples to develop a holistic understanding of this complex process. In Specific Aim 3, the information gained during this examination will be used to inform the design of immuno- modulatory hemostatic biomaterials for potential use in trauma patients. Gaining the fundamental knowledge proposed here will inform the understanding of bleeding and hemostasis, the interplay between fibrin and inflammatory cells, and the use of fibrin in biomaterials. During the mentored phases I will gain the background and experimental skills needed to accomplish the proposed research under the guidance of the mentoring team and collaborators and give me the foundation to take a multidisciplinary approach to this important and understudied area of research. Importantly, my mentoring team has a strong track record in training post-doctoral fellows for a transition into a career as an independent investigator and will foster the growth of not only my research skills but also my leadership, mentoring, and professional development acumen. Combining the new skills learned during the K99 mentored phase with my prior expertise in hemostasis, thrombosis, and clot contraction will uniquely position me to take a multidisciplinary approach to studying blood biomaterial interactions and allow me to launch an independent and distinct laboratory that can impact a variety of fields.