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: 10693828
• 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/10693828
• 关键词: Academic Medical Centers; Allografting; Attenuated; Automobile Driving; Award; Basic Science; Biological Markers; Biomedical Engineering; Blood Coagulation Disorders; Blood Vessels; Characteristics; Clinical; Clinical Research; Coagulation Process; Colorado; Complex; Costs and Benefits; Data; Databases; Donor person; Environment; 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; Liver; 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; Research Training; Resistance; Risk; Role; Running; Scientist; Source; Surgeon; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thrombophilia; Thrombosis; Time; Tissues; Training; Translating; Translations; Transplant Recipients; Transplantation; Transplantation Surgery; Trauma; United States; United States National Institutes of Health; Universities; Visceral; career; clinical practice; clinical training; effective therapy; end stage liver disease; experience; graft dysfunction; 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.

项目摘要/摘要 这是亨特·摩尔博士（Hunter Moore 科罗拉多州医学院。摩尔博士正在以患者为导向的年轻调查员建立自己 对纤维蛋白溶解和器官衰竭的翻译研究进行研究。这个K99奖将为他提供 实现以下目标所必需的指导支持； 1）建立预期的结果注册表 确定与移植功能障碍相关的变量，2） 量化纤维蛋白溶解，3）整合临床和翻译数据以形成机械假设 推动低纤维蛋白溶解的因素4）作为医师科学家成熟的临床培训的同时成功。 Moore博士得到了专业的多学科导师团队的支持。米奇·科恩（Mitch Cohen）博士将是他的主要导师。 他曾是K-08的前获奖者，目前指导了另外三名K奖者。科恩博士一直是 数十年来研究凝血病，目前经营着大型NIH和DOD资助的实验室 学术医学中心手术主席。他将提供建立成功的指导 除了平衡临床和研究努力外，基于翻译凝血的实验室。摩尔博士 有两位基础科学指导者：（1）Kirk Hansen博士，质谱学公认的专家； he has 开发了定义组织特异性蛋白质组学的方法，该方法将提供新颖的研究方法 （2）基于基于流动的凝结专家Keith Neeves博士，了解局部水平的纤维蛋白溶解；他的 生物工程专业知识为模拟微脉管系统的建筑模型提供了指导。博士 Angela Sauaia是公共卫生学院的教授，在翻译方面拥有丰富的经验 凝血研究；她将担任指导，以建立关注移植功能的结果数据库。她 分析纵向数据和可变减少技术的专业知识对于培训摩尔博士至关重要 在检查受体中纤维蛋白溶解的时间变化时，以及复杂的相互作用 在捐助者和接收者之间。最终的核心导师是Trevor Nydam博士，他完成了移植 科罗拉多大学的奖学金是目前的奖学金计划主任。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将每月开会并进行调整 根据需要进行保护和临床培训，以达到父母应用中的里程碑。摩尔·威尔博士 研究AIM 1的供体器官器官器官器官中的低纤维蛋白溶解和微血管凝块的关联 其次是AIM 2，定义了低纤维蛋白溶解与肝脏早期移植功能受损之间的关联 移植接受者。 AIM 3将评估供体器官局部蛋白质组对形成纤维蛋白溶解的影响 凝块。这些目标将提供有关驾驶微血管的门，器官和受体的相互作用的见解 血栓形成，使能够在该赠款的R00成熟中检验机械假设的形成。

项目成果

Low viscoelastic clot strength, platelet transfusions, and graft dysfunction are associated with persistent postoperative ascites following liver transplantation.

• DOI: 10.1016/j.amjsurg.2022.09.054
• 发表时间: 2022-12
• 期刊: AMERICAN JOURNAL OF SURGERY
• 影响因子: 3
• 作者: Jiang, Jessie G.;Ferrell, Tanner;Sauaia, Angela;Rodriguez, Ivan E.;Yoeli, Dor;Nydam, Trevor L.;Kennealey, Peter T.;Pomposelli, James J.;Pomfret, Elizabeth A.;Moore, Hunter B.
• 通讯作者: Moore, Hunter B.

Fibrinolysis resistance after liver transplant as a predictor of early infection.

• DOI: 10.1016/j.amjsurg.2022.09.011
• 发表时间: 2022-12
• 期刊: AMERICAN JOURNAL OF SURGERY
• 影响因子: 3
• 作者: Rodriguez, Ivan E.;Yoeli, Dor;Ferrell, Tanner;Jiang, Jessie G.;Truong, Ronald;Nydam, Trevor L.;Adams, Megan A.;Cullen, J. Michael;Pomfret, Elizabeth A.;Moore, Hunter B.
• 通讯作者: Moore, Hunter B.

MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study.

• DOI: 10.1002/rth2.12669
• 发表时间: 2022-03
• 期刊: Research and practice in thrombosis and haemostasis
• 影响因子: 4.6
• 作者: Barrett CD;Moore HB;Moore EE;Benjamin Christie D 3rd;Orfanos S;Anez-Bustillos L;Jhunjhunwala R;Hussain S;Shaefi S;Wang J;Hajizadeh N;Baedorf-Kassis EN;Al-Shammaa A;Capers K;Banner-Goodspeed V;Wright FL;Bull T;Moore PK;Nemec H;Thomas Buchanan J;Nonnemacher C;Rajcooar N;Ramdeo R;Yacoub M;Guevara A;Espinal A;Hattar L;Moraco A;McIntyre R;Talmor DS;Sauaia A;Yaffe MB
• 通讯作者: Yaffe MB