Ischemia-reperfusion injury in liver transplantation

肝移植中的缺血再灌注损伤

• 批准号: 10218143
• 负责人: ALI ZARRINPAR
• 金额: $ 15.48万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218143
• 关键词: Academic Training; Acute; Affect; Agammaglobulinaemia tyrosine kinase; Anatomy; Antibodies; Antigens; Biopsy; Blood specimen; Cell Death; Cells; Cellular biology; Clinical; Clinical Data; Data; Development; Development Plans; Disease; Doctor of Philosophy; Ensure; Future; Grant; Hepatic; Hepatocellular Damage; Hospitalization; Human; Immune; Immune response; Immunologics; Immunology; In Situ; In Vitro; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Isoantibodies; Kinetics; Knockout Mice; Kupffer Cells; Laboratories; Lead; Learning; Liver; Lymphocyte; Measures; Mediating; Medical History; Mentors; Metabolic; Microscopy; Modeling; Monitor; Mononuclear; Mus; Myocardial Infarction; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Operative Surgical Procedures; Organ; Organ Transplantation; Organ failure; Outcome; Pathologic; Patients; Peripheral Vascular Diseases; Physicians; Process; Recruitment Activity; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Role; Sampling; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Source; Specimen; Standardization; Stroke; Surgeon; T-Lymphocyte; Testing; Tissues; Training; Transfusion; Transplant Recipients; Transplantation; Trauma; Tyrosine Kinase Inhibitor; Warm Ischemia; base; career; career development; cytokine; expectation; experience; experimental study; graft function; hepatocellular injury; histopathological examination; improved; in vivo; liver allograft; liver ischemia; liver transplantation; macrophage; monocyte; mouse model; neutrophil; novel therapeutics; operation; peripheral blood; post-transplant; predicting response; profiles in patients; programs; recruit; response; small molecule inhibitor

PROJECT SUMMARY The candidate, Dr. Ali Zarrinpar, presents a 5-year career development plan that seeks to characterize the relationship between pre-transplant neutrophil activity, ischemia/reperfusion injury (IRI), and eventual transplant outcomes while establishing an academic career as a physician-scientist in the field of surgery. IRI is the principal mechanism by which diseases such as myocardial infarction, stroke, and peripheral vascular disease cause their damage. It is also a major source of graft injury during organ transplantation. He and his colleagues have found that Bruton's tyrosine kinase (Btk) activity is important in liver IRI. Its selective inhibition blocks IR-induced hepatocellular damage and as a result protects the liver from subsequent severe inflammation. They also have conducted studies using specimens from human liver transplant recipients and found cytokines present in pre-transplant sera of recipients that predict the severity of IRI. These data suggest that recipients' pre-transplant immunologic milieu can influence IRI. These data have led them to hypothesize that measuring and modulating pre-transplant neutrophil activity will permit the selection, monitoring, and modulation of IRI, thereby improving liver transplant outcomes. This hypothesis will be pursued with two specific aims that investigate the relationship between neutrophil activity and IRI. Specific aim 1 tests the hypothesis that Btk activation potentiates neutrophil activation and promotes innate immune activity. This hypothesis will be tested both in vitro and in vivo using murine models. Specific aim 2 tests the hypothesis that heightened neutrophil activity before transplantation leads to increased IRI and subsequent activation of resident Kupffer cells and recruitment/activation of monocytes/macrophages and circulating T cells in human liver allografts, and that this pathological cascade perpetuates damage to the graft. This hypothesis will be tested using samples from human liver transplantation operations. Dr. Zarrinpar is well qualified to carry out the research outlined in this proposal. He has successfully completed projects of comparable complexity as part of his PhD thesis. He will train further by acquiring expertise in high quality IRI experiments and by studying immunology and cell biology. His mentor Dr. Jerzy Kupiec-Weglinski has decades long experience in studying transplant immunology and IRI. His co-mentor Dr. Stephen Bensinger provides expertise in studying the cell biology, signaling, and metabolic factors affecting the immune response. Dr. Ronald Busuttil, who has extensive experience training academic surgeons, will advise him on major career related issues and help navigate the academic promotion process. He will meet with his mentor and co-mentor monthly and meet with his surgical mentor every three months to discuss progress and to ensure a successful scientific program. Successful completion of the specific aims and career development plan outlined in this proposal will allow Dr. Zarrinpar to learn how to perform high quality immunology studies and to develop into an independent investigator in the field of surgery and immunology.

项目摘要 候选人Ali Zarrinpar博士提出了一项为期5年的职业发展计划，旨在表征 移植前中性粒细胞活性，缺血/再灌注损伤（IRI）与最终之间的关系 在手术领域担任医师科学家的学术生涯时，可以移植成果。艾里 是心肌梗塞，中风和周围血管等疾病的主要机制 疾病会造成伤害。它也是器官移植期间移植损伤的主要来源。他和他的 同事发现布鲁顿的酪氨酸激酶（BTK）活性在肝脏IRI中很重要。它的选择性抑制 阻断IR诱导的肝细胞损伤，因此保护肝脏免受随后的严重性 炎。他们还使用人肝移植受者的标本进行了研究 发现了预测IRI严重程度的受体的移植前血清中存在的细胞因子。这些数据暗示 该接受者移植前免疫环境可能会影响IRI。 这些数据使他们假设测量和调节移植前中性粒细胞活性将 允许对IRI的选择，监测和调节，从而改善肝脏移植结果。这 假设将以两个具体的目的来提出假设，以研究中性粒细胞活性之间的关系 和iri。特定目标1检验了BTK激活增强中性粒细胞激活并促进的假设 先天免疫活动。该假设将在体外和体内使用鼠模型进行检验。具体的 AIM 2检验以下假设：移植前中性粒细胞的活性提高导致IRI和 随后的居民库普弗细胞的激活以及单核细胞/巨噬细胞的募集/激活 人肝移植中循环T细胞，这种病理级联对移植物的损害永存。 该假设将使用来自人类肝移植操作的样品进行检验。 Zarrinpar博士有资格进行此提案中概述的研究。他已经成功完成 作为他的博士学位论文的一部分，具有可比复杂性的项目。他将通过获得高处的专业知识来进一步培训 质量IRI实验以及研究免疫学和细胞生物学。他的导师Jerzy Kupiec-Weglinski博士 在研究移植免疫学和IRI方面拥有数十年的长期经验。他的同事斯蒂芬·本辛格（Stephen Bensinger）博士 在研究影响免疫反应的细胞生物学，信号传导和代谢因素方面提供了专业知识。 拥有丰富经验培训学术外科医生的Ronald Busuttil博士将为他提供有关主要职业的建议 相关问题并有助于浏览学术晋升过程。他将与他的导师和联合主管见面 每月一次，每三个月与他的手术导师会面，讨论进度并确保成功 科学计划。成功完成了特定目标和职业发展计划 提案将使Zarrinpar博士学习如何进行高质量免疫学研究并发展成 手术和免疫学领域的独立研究者。