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

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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.