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Ischemia-reperfusion injury in liver transplantation

肝移植中的缺血再灌注损伤

基本信息

批准号：
9753214
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753214
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 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

项目摘要

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.

项目总结