Ischemia-reperfusion injury in liver transplantation

项目总结 候选人阿里·扎林帕尔博士提出了一项5年职业发展计划，试图描述 移植前中性粒细胞活性、缺血/再灌注损伤(IRI)与最终死亡的关系 移植结果，同时建立作为外科领域的内科科学家的学术生涯。IRI 是心肌梗死、中风和外周血管等疾病的主要机制 疾病会造成他们的损害。它也是器官移植过程中移植物损伤的主要来源。他和他的 同事们发现，Bruton的酪氨酸激酶(BTK)活性在肝脏IRI中很重要。它的选择性抑制作用 阻断IR诱导的肝细胞损伤，从而保护肝脏免受随后严重的 发炎。他们还利用人类肝脏移植受者的样本进行了研究，并 发现受体移植前血清中存在的细胞因子可以预测IRI的严重程度。这些数据表明 受者移植前的免疫环境会影响IRI。 这些数据使他们假设，测量和调节移植前的中性粒细胞活性将 允许选择、监测和调节IRI，从而改善肝脏移植的结果。这 这个假说有两个特定的目的来研究中性粒细胞活性之间的关系 还有IRI。特异性目标1验证BTK激活增强中性粒细胞激活并促进 先天免疫活性。这一假说将在体外和体内使用小鼠模型进行验证。特定的 目的2验证移植前中性粒细胞活性升高会导致IRI增加和 随后激活常驻Kupffer细胞和招募/激活单核/巨噬细胞和 人类同种异体肝移植中的循环T细胞，这种病理性的级联反应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验证。 扎林帕尔博士完全有资格开展这项提案中概述的研究。他已经成功地完成了 相当复杂的项目作为他博士论文的一部分。他将通过获得高中的专业知识来进行进一步的训练 高质量的IRI实验，并通过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。他的合作导师斯蒂芬·本辛格博士 在研究影响免疫反应的细胞生物学、信号和代谢因素方面提供专业知识。 罗纳德·布苏蒂尔博士拥有丰富的学术外科医生培训经验，他将为他的主要职业生涯提供建议。 相关问题，并帮助驾驭学术晋升过程。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，确保成功 科学计划。圆满完成本文件中概述的具体目标和职业发展计划 提案将允许扎林帕尔博士学习如何进行高质量的免疫学研究，并发展成 外科和免疫学领域的独立研究员。

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.