Antigen-indepenendent CD8 T cell-induced Hepatitis

描述(由申请人提供)：这份建议书概述了一个职业发展计划，目标是在病理学领域发展一个成功的学术生涯。首席研究员(PI)是罗切斯特大学医学院(UR)病理学专业的助理教授。他是美国病理委员会的外交官，拥有丰富的临床和教学经验。这项指导临床科学家奖(KO8)的建议将通过一个为期5年的教育和研究计划，促进在肝脏免疫病理学领域获得基础研究专业知识，重点是抗原非依赖性CD8 T细胞诱导的肝脏损伤的机制。 肝脏似乎在消除CD8T淋巴细胞活化诱导的凋亡过程中发挥着独特的作用。我们目前对这种T细胞清除机制的理解主要是基于PI的导师Crispe博士的工作，他使用了表达转基因T细胞受体(TCR)的小鼠模型。靶肽与这些转基因T细胞结合后会引起克隆性扩增，导致肝脏选择性摄取这些T细胞并随后死亡。由于肝脏中持续的淋巴细胞凋亡，血清转氨酶水平升高，表明在肝细胞缺乏靶抗原表达的情况下肝细胞受到损伤。PI实验室最近的工作证明了肝炎，在转基因TCR模型和流感感染中，由含有CD8 T细胞和Kupffer细胞的细胞渗透组成。这些数据表明，这种现象可能代表了对CD8T细胞群扩大的普遍反应和肝损伤的共同途径，这可能具有重要的临床意义。本研究将探讨这种新型抗原非依赖性CD8T细胞诱导肝炎的机制。克里斯佩博士是新兴的肝脏特异性免疫生物学领域的领导者之一，作为一名导师，他有着出色的记录。此外，一个由另外3名资深科学家组成的职业发展咨询委员会将向PI提供咨询和指导。总体而言，UR提供了一个出色的环境，提供了一流的设施，并营造了一种支持和合作的氛围。这一结构化和有指导的计划将促进PI作为研究人员向独立的方向发展，最终在未来的RO1应用于肝脏免疫病理领域。

DESCRIPTION (provided by applicant): This proposal outlines a career development program with the goal of developing a successful academic career in Pathology. The principal investigator (PI) is an Assistant Professor with a tenuretrack appointment in Pathology at the University of Rochester School of Medicine (UR). He is a diplomat of the American Board of Pathology and possesses significant clinical and teaching experience. This Mentored Clinical Scientist Award (KO8) proposal will facilitate the acquisition of basic research expertise in the area of liver immuno- pathology through a 5 year educational and research program focusing on the mechanism of antigen-independent CD8 T cell -induced liver damage. The liver appears to play a unique role in the elimination of CD8 T lymphocytes undergoing activation-induced apoptosis. Our current understanding of this mechanism of T cell clearance is based largely on the work of Dr. Crispe, the PI's Mentor, using mouse models expressing transgenic T cell receptors (TCR). Binding of target peptide to these transgenic T cells causes a clonal expansion, resulting in their selective uptake by the liver and subsequent death. As a consequence of this ongoing lymphocyte apoptosis in the liver, serum transaminase levels increase, indicating hepatocyte injury in the absence of hepatocyte expression of target antigen. Recent work in the PI's laboratory has demonstrated hepatitis, consisting of cellular infiltrates containing both CD8 T celland Kupffer cells both in the transgenic TCR model as well as in influenza infection. These data suggest that this phenomenon may represent a general response to expanded CD8 T cell populations and a common pathway of liver injury, which may have significant clinical implications. This study will investigate the mechanism of this novel antigen-independent CD8 T cell-induced hepatitis. Dr. Crispe is one of the leaders in the emerging area of liver-specific immunobiology and has an excellent track record as a mentor. In addition, a career development advisory committee consisting of 3 additional senior scientists will provide advice and guidance to the PI. Overall, the UR provides an outstanding setting by providing both excellent facilities and by fostering an atmosphere of support and collaboration. This structured and mentored program will facilitate the PI's evolution to independence as an investigator, culminating in a future RO1 application in the area of liver immunopathology.