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起着至关重要的作用 （病原）生理条件引起的血液凝块的稳定性。纤维蛋白原 创伤性损伤后的血液迅速枯竭，这可能导致 凝血病，或出血；这与死亡风险增加和 适应性炎症反应。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证据表明纤维蛋白原，纤维蛋白和凝块结构 是血小板疾病的关键驱动因素。但是，关于如何改变的知之甚少 创伤性凝血病期间的纤维蛋白原和纤维蛋白血块形成可能会连接止血， 创伤后的炎症和免疫力。在特定的目标1中，我建议进行多学科 系统地检查血凝块形成，结构，力学和纤维蛋白水解的方法 创伤设置中的特性。在特定目标2中，我计划检查纤维蛋白之间的相互作用 以及凝血病中的炎性细胞，巨噬细胞。尖端实验，成像， 并且机械测试技术将在体外和体内测定中使用，并在体内进行重组 和患者样本以对这一复杂过程有整体理解。在特定目标中 3，在此考试中获得的信息将用于告知免疫的设计 调节性止血生物材料，用于创伤患者的潜在用途。获得基本 这里提出的知识将告知人们对出血和止血的理解， 在纤维蛋白和炎性细胞之间，以及在生物材料中使用纤维蛋白。在指导期间 阶段我将获得完成提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，并给我基础 采用多学科的方法来解决这一重要且研究的研究领域。 重要的是，我的指导团队在训练博士后研究员方面拥有良好的记录 过渡为独立调查员的职业，不仅会促进我的成长 研究技能，也是我的领导，指导和专业发展敏锐度。 将K99指导阶段中学到的新技能与我先前的专业知识相结合 止血，血栓形成和凝块收缩将使我唯一地放置多学科 研究血液生物材料相互作用的方法，使我能够启动独立和 可能影响各个领域的独特实验室。