Ischemia-reperfusion injury in liver transplantation

项目摘要 候选人Ali Zarrinpar博士提出了一个5年职业发展计划，旨在描述 移植前中性粒细胞活性、缺血/再灌注损伤（IRI）和最终 移植的结果，同时建立一个学术生涯作为一个医生，科学家在外科领域。IRI 是心肌梗死、中风和外周血管疾病的主要机制， 疾病造成的伤害。它也是器官移植过程中移植物损伤的主要来源。他和他 同事们发现布鲁顿的酪氨酸激酶（Btk）活性在肝脏IRI中很重要。其选择性抑制 阻断IR诱导的肝细胞损伤，从而保护肝脏免受随后的严重 炎症他们还使用人类肝移植受者的标本进行了研究， 发现细胞因子存在于移植前受者血清中，可预测IRI的严重程度。这些数据表明 受者移植前的免疫环境可以影响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， 允许选择、监测和调节IRI，从而改善肝移植结果。这 本研究将以两个特定的目的来探讨中性粒细胞活性与 和IRI。具体目的1检验Btk活化增强中性粒细胞活化并促进中性粒细胞活化的假设。 先天免疫活性将使用鼠模型在体外和体内检验该假设。具体 目的2检验移植前中性粒细胞活性升高导致IRI增加的假设， 随后激活驻留库普弗细胞和募集/激活单核细胞/巨噬细胞， 循环T细胞在人类肝脏同种异体移植物中，并且这种病理级联使移植物的损害永久化。 这一假设将使用来自人类肝移植手术的样本进行检验。 博士Zarrinpar完全有资格进行本提案中概述的研究。他成功地完成了 作为他博士论文的一部分。他将通过获得高等教育方面的专业知识， 高质量的IRI实验和学习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方面有数十年的经验。他的共同导师斯蒂芬·本辛格博士 提供研究细胞生物学，信号传导和影响免疫反应的代谢因素的专业知识。 博士罗纳德布苏蒂尔，谁拥有丰富的经验培训学术外科医生，将建议他的主要职业生涯 相关问题，并帮助导航学术推广过程。他将会见他的导师和共同导师 每月一次，每三个月与他的外科导师会面，讨论进展情况，并确保成功 科学计划。成功地完成了具体目标和职业发展计划， 该提案将使Zarrinpar博士能够学习如何进行高质量的免疫学研究，并发展成为 外科和免疫学领域的独立研究者。

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.