Fibrinolysis Dysfunction Impact on Graft Function in Liver Transplantation

项目摘要/摘要 这是亨特·摩尔博士的K99奖申请表，他是加州大学的移植外科研究员。 科罗拉多医学院。摩尔医生在《以病人为本》中确立了自己作为一名年轻研究员的地位 专注于纤溶和器官衰竭的翻译研究。这一K99奖项将为他提供 完成以下目标所需的有指导的支持：1)建立预期成果登记册 为了确定与移植物功能障碍相关的变量，2)高级基础科学方法论培训 量化纤溶，3)整合临床和翻译数据以形成机制假说 导致纤溶功能低下的因素4)临床培训与作为内科科学家的成熟同时取得成功。 摩尔博士得到了一个专业的多学科导师团队的支持。米奇·科恩博士将是他的主要导师； 他是一名前K-08获奖者，目前指导着另外三名K奖获得者。科恩博士一直在 研究凝血障碍数十年，目前经营着一家由NIH和国防部资助的大型实验室，同时担任 学术医学中心的外科主任。他将为建立一个成功的 以转化性凝血为基础的实验室，以及平衡临床和研究努力。摩尔博士 有两位基础科学导师：(1)柯克·汉森博士，公认的质谱学专家；他有 开发了定义组织特定蛋白质组学的方法，这将提供新的研究方法 了解局部水平的纤溶，(2)血流凝血专家基思·尼维斯博士；他的 生物工程的专业知识为建立模拟微血管系统的模型提供了指导。Dr。 Angela Sauaia是公共卫生学院的教授，在翻译方面有丰富的经验 凝血研究；她将在建立专注于移植物功能的结果数据库方面担任导师。她 分析纵向数据和变量简化技术的专业知识将是培训摩尔博士的关键 在检查受者纤溶功能随时间的时间变化以及复杂的相互作用方面 捐赠者和接受者之间的关系。最后一位核心导师是特雷弗·尼达姆博士，他完成了他的移植 他是科罗拉多大学奖学金项目的现任主任。他对临床的洞察力 责任和研究是成功的关键。尼达姆博士和摩尔博士将每月见面并进行调整 根据需要进行保护性研究和临床培训，以达到母公司应用程序中的里程碑。摩尔博士会 研究捐赠者器官中低纤溶与微血管凝块的关系，目的1， 其次是目标2，确定低纤溶与肝脏早期移植功能受损之间的联系 移植受者。目的3将评估供体器官局部蛋白质组在形成纤溶抵抗中的作用 血栓。这些目标将提供对门、器官和受体驱动微血管的相互作用的洞察力 血栓形成，使机械假说的形成可以在这笔赠款的R00成熟期进行测试。

PROJECT SUMMARY/ABSTRACT 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.