This is an application for a K99 award for Dr. Hunter Moore, a transplant surgery fellow at the University of Colorado School of Medicine. Dr. Moore is establishing himself as a young investigator in patient-oriented research with a translational focus on fibrinolysis and organ failure. This K99 award will provide him with the mentored support necessary to accomplish the following goals; 1) Establishing a prospective outcome registry to identify variables associated with graft dysfunction, 2) Training in advanced basic science methodologies of quantifying fibrinolysis, 3) Integration of clinical and translation data to form a mechanistic hypothesis for factors driving low fibrinolysis 4) Concurrent success in clinical training with maturation as a physician scientist. Dr. Moore is supported by an expert multidisciplinary mentor team. Dr. Mitch Cohen will be his primary mentor; he is a former K-08 recipient, and currently mentors three additional K award recipients. Dr. Cohen has been researching coagulopathy for decades and currently runs a large NIH and DoD funded lab while serving as the Chair of Surgery at an academic medical center. He will provide mentoring on establishing a successful translational coagulation-based laboratory in addition to balancing clinical and research endeavors. Dr. Moore has two basic science mentors: (1) Dr. Kirk Hansen, a recognized expert on mass spectrometry; he has developed methods for defining tissue-specific proteomics, which will provide novel research approaches to understand fibrinolysis at a local level, (2) Dr. Keith Neeves, an expert on flow-based coagulation; his bioengineering expertise provides the mentorship for building models that simulate the microvasculature. Dr. Angela Sauaia is a Professor in the School of Public Health, with extensive experience in translational coagulation research; she will act as a mentor in building an outcomes database focused on graft function. Her expertise in analyzing longitudinal data and variable reduction techniques will be critical for training Dr. Moore in examining the temporal changes in fibrinolysis over time in the recipient, as well as the complex interactions between the donor and recipient. The final core mentor is Dr. Trevor Nydam, who completed his transplant fellowship at the University of Colorado and is the current fellowship program director. His insight in clinical responsibilities and research are critical for success. Drs. Nydam and Moore will meet monthly and adjust protected research and clinical training as needed to reach milestones in the parent application. Dr. Moore will investigate the association of low fibrinolysis and microvascular clots in the organs of donors for Aim 1, followed by Aim 2, defining the association between low fibrinolysis and impaired early graft function in liver transplant recipients.
Aim 3 will assess the donor organ local proteomes effect on forming fibrinolysis resistant clots.
These aims will provide insight on the interaction of the door, organ, and recipients driving microvascular thrombosis, enabling the formation of a mechanistic hypothesis to be tested in the R00 maturation of this grant.
This proposed project is relevant to the United States health care system as thousands of preventable deaths occur per year due to scarcity of livers available for transplantation, which is the only treatment of end stage liver disease. Expanding the organ donor pool to attenuate this problem has resulted in the reduction in the quality of organs, with 1 in 4 liver transplant recipients suffering from early allograft dysfunction (EAD), which is associated with early graft loss and early mortality. EAD persists as an untreated morbidity in liver transplant recipients due to our poor understanding of its mechanisms; while low fibrinolysis (also termed fibrinolysis shutdown) has been implicated in driving organ failure in other clinical settings, its role in driving EAD has not been previously evaluated, and likely provides a therapeutic target to improve organ function after transplantation.