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

系统性多学科方法将创伤性出血作为复杂的结构和生物力学问题进行研究

• 批准号: 9806262
• 负责人: Valerie Tutwiler
• 金额: $ 9.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806262
• 关键词: Acute; Affect; Area; Biochemical; Biocompatible Materials; Biological Assay; Biomaterials Research; Biomechanics; Blood; Blood Coagulation Disorders; Blood coagulation; Cause of Death; Cells; Cellular Immunity; Cessation of life; Coagulation Process; Coculture Techniques; Complex; Coupled; Development; Early-life trauma; Engineering; Environment; Failure; Fibrin; Fibrinogen; Finite Element Analysis; Fostering; Foundations; Growth; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Human Biology; Image; Immune; Immune response; Immunity; Immunoassay; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Laboratories; Lead; Leadership; Leukocytes; Link; Lytic; Measures; Mechanics; Mentors; Mission; Modeling; National Heart, Lung, and Blood Institute; Optics; Patients; Phase; Phenotype; Physiological; Plasma; Plasma Proteins; Play; Polymers; Positioning Attribute; Process; Property; Radiolabeled; Rattus; Research; Research Personnel; Rheology; Risk; Role; Sampling; Scanning Electron Microscopy; Structure; Techniques; Testing; Thrombosis; Trauma; Trauma patient; Traumatic injury; Wound Healing; base; career; design; experimental study; healing; immunoregulation; improved outcome; in vivo; inflammatory marker; insight; interdisciplinary approach; macrophage; mathematical model; mortality; mortality risk; multi-scale modeling; novel; post-doctoral training; prevent; reconstitution; response; skills

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.

项目摘要 纤维蛋白在止血、血栓形成和伤口愈合中发挥着关键作用，它通过提供机械 对因(病理)生理条件而变形的血液凝块的稳定性。纤维蛋白原 在创伤后迅速从血液中耗尽，这可能导致 凝血障碍，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 年轻人。我们已经收集了相当多的证据证明纤维蛋白原、纤维蛋白和凝块结构 是血栓性疾病的关键驱动因素。然而，人们对生物多样性的变化知之甚少。 纤维蛋白原和纤维蛋白凝块在创伤凝血障碍中的形成可能与止血有关， 炎症和创伤后的免疫力。在具体目标1中，我建议采取多学科的 系统检查血栓形成、结构、力学和纤溶的方法 在创伤环境中的财产。在特定的目标2中，我计划研究纤维蛋白之间的相互作用 以及炎症细胞，巨噬细胞，在凝血障碍中。尖端实验、成像、 和机械测试技术将使用体外和体内测试，两者重组 和患者样本，以发展对这一复杂过程的整体理解。以特定的目标 3、在这次检查中获得的信息将被用来为免疫系统的设计提供参考 可调节止血生物材料在创伤患者中的潜在应用。获取基本信息 这里提出的知识将有助于理解出血和止血的相互作用 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。在接受指导的过程中 第一阶段将获得实现建议的背景和实验技能 在指导团队和合作者的指导下进行研究，并为我提供基础 对这一重要而研究不足的领域采取多学科方法。 重要的是，我的指导团队在培训博士后研究员方面有很好的记录 过渡到独立调查员的职业生涯，不仅将促进我的成长 除了研究技能，还有我的领导力、指导和职业发展的敏锐性。 将在K99指导阶段学到的新技能与我以前在 止血、血栓形成和血栓收缩将使我处于独特的地位，可以参加一个多学科的 研究血液生物材料相互作用的方法，并允许我发起一个独立和 独特的实验室，可以影响到各种领域。