Fibrinolysis Dysfunction Impact on Graft Function in Liver Transplantation

肝移植中纤溶功能障碍对移植物功能的影响

• 批准号: 10445405
• 负责人: Hunter B Moore
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445405
• 关键词: Academic Medical Centers; Allografting; Attenuated; Automobile Driving; Award; Basic Science; Biological Markers; Biomedical Engineering; Blood Coagulation Disorders; Characteristics; Clinical; Clinical Research; Coagulation Process; Colorado; Complex; Costs and Benefits; Data; Databases; Donor person; Environment; Equilibrium; Extramural Activities; Failure; Fellowship; Fellowship Program; Fibrinolysis; Functional disorder; Funding; Goals; Grant; Health; Healthcare Systems; Impairment; Intensive Care Units; K-Series Research Career Programs; Laboratories; Lead; Liver; Liver diseases; Longevity; Mass Spectrum Analysis; Mentors; Mentorship; Methodology; Methods; Morbidity - disease rate; Operative Surgical Procedures; Organ; Organ Donations; Organ Donor; Organ failure; Outcome; Parents; Patient-Focused Outcomes; Patients; Physicians; Proteins; Proteome; Proteomics; Public Health Schools; Registries; Research; Research Personnel; Resistance; Risk; Role; Running; Scientist; Source; Surgeon; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thrombophilia; Thrombosis; Time; Tissues; Training; Translating; Transplant Recipients; Transplantation; Transplantation Surgery; Trauma; United States; United States National Institutes of Health; Universities; Visceral; base; career; clinical practice; clinical translation; effective therapy; experience; graft function; improved; insight; interest; liver transplantation; longitudinal analysis; medical schools; model building; mortality; multidisciplinary; novel; patient oriented research; prevent; preventable death; professor; prospective; proteomic signature; severe injury; success; therapeutic target

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.

项目概要/摘要 这是亨特·摩尔 (Hunter Moore) 博士的 K99 奖申请，他是纽约大学移植外科研究员 科罗拉多医学院。摩尔博士正在将自己定位为以患者为中心的年轻研究者 重点关注纤维蛋白溶解和器官衰竭的转化研究。这个K99奖项将为他提供 实现以下目标所需的指导支持； 1) 建立前瞻性结果登记处 识别与移植功能障碍相关的变量，2) 先进基础科学方法的培训 量化纤维蛋白溶解，3) 整合临床和翻译数据以形成机制假设 导致低纤维蛋白溶解的因素 4) 在临床培训中取得成功，同时成为一名成熟的医师科学家。 摩尔博士得到了多学科专家导师团队的支持。米奇·科恩博士将成为他的主要导师； 他是前 K-08 获得者，目前指导另外三名 K 奖获得者。科恩博士曾 研究凝血病数十年，目前运营着一个由 NIH 和 DoD 资助的大型实验室，同时担任 学术医疗中心的外科主任。他将为建立成功的 除了平衡临床和研究工作外，还建立了基于转化凝血的实验室。摩尔博士 有两位基础科学导师：（1）Kirk Hansen博士，公认的质谱专家；他有 开发了定义组织特异性蛋白质组学的方法，这将为以下方面提供新的研究方法： 了解局部纤维蛋白溶解情况，(2) Keith Neeves 博士，血流凝血专家；他的 生物工程专业知识为构建模拟微脉管系统的模型提供了指导。博士。 Angela Sauaia 是公共卫生学院的教授，在转化方面拥有丰富的经验 凝血研究；她将作为导师建立一个专注于移植功能的结果数据库。她 分析纵向数据和变量缩减技术的专业知识对于培训摩尔博士至关重要 检查受者体内纤维蛋白溶解随时间的变化，以及复杂的相互作用 捐赠者和接受者之间。最后一位核心导师是Trevor Nydam博士，他完成了移植手术 科罗拉多大学研究员，现任奖学金项目主任。他对临床的见解 责任和研究对于成功至关重要。博士。 Nydam 和 Moore 将每月会面并进行调整 根据需要保护研究和临床培训，以达到母申请中的里程碑。摩尔博士将 研究目标 1 的捐献者器官中低纤维蛋白溶解和微血管血栓的关联， 其次是目标 2，定义低纤维蛋白溶解与肝脏早期移植功能受损之间的关联 移植受者。目标 3 将评估供体器官局部蛋白质组对形成纤溶抗性的影响 凝块。这些目标将深入了解驱动微血管的门、器官和受体之间的相互作用 血栓形成，从而能够形成机制假说，并在本次拨款的 R00 成熟期中进行测试。