Defining Immunology Frailty as a Predictor of Human Liver Allograft Recipient Futility

项目总结/摘要 描述：本申请指导临床医生科学家发展奖（K 08）旨在 评估炎症诱导的免疫功能障碍对肝移植结果的影响。候选人是 移植外科医生和免疫学家，其长期目标是开发预防免疫脆弱的治疗方法， 提高肝移植受者存活率。为了实现本奖项的教育目标，本提案 将扩大申请人的知识基础到翻译研究调查的新线路，并深入研究新的 需要重点指导的调查领域。协助申请人发展的导师将是 这对她的成功、对拟议研究的表现以及对该奖项的教育使命至关重要。 基础科学免疫学领域的领导者Xian Li博士和临床和免疫学领域的领导者Mark Ghobrial博士 翻译研究，将担任共同导师。他们将由戴尔汉密尔顿和阿妮莎古普特博士协助， 他将提供生物能量学方面的指导;艾德·格拉维斯博士，他将提供生物统计学方面的专业知识; Wenhao Chen将提供T细胞耗竭方面的专业知识，托德·卡萨尔博士将提供T细胞耗竭方面的专业知识。 炎症将实施严格的职业发展计划，包括举办结构化讲习班， 生物统计学课程作业、科学研讨会和实验室会议。这种结合将有助于确保 候选人成功转型为独立调查员。 项目概要：由于器官短缺，肝脏移植是按照接受者的医疗紧急程度进行的; 然而，道德原则要求避免无效的移植。由于供求不平衡， 器官，疾病严重程度（按MELD评分分类）急剧增加。MELD与 移植后死亡的风险;因此，需要更好的指标来评估死亡风险。最常见的 肝移植后早期死亡的原因与免疫系统脆弱或 在移植前功能失调。在移植前免疫系统中，免疫脆弱可能与代谢缺陷有关， T细胞耗竭，可能影响肝移植结果。基于此，假设移植前 免疫虚弱状态是由于受体代谢中与肿瘤相关的改变，导致整体T细胞减少。 细胞代谢功能障碍、T细胞衰竭增加以及适应性免疫增殖和功能受限。 肝移植后免疫功能持续低下导致受体死亡率增加。这将是 通过三个目标解决，这将（1）评估肝移植受者的代谢改变，并确定 参与免疫虚弱的生物能量学途径，（2）检查T细胞耗竭在免疫虚弱中的作用， 和（3）确定虚弱对受体移植后免疫应答的纵向影响。 影响：这些研究对于识别免疫脆弱的生物标志物至关重要。定义前- 移植虚弱将改善肝移植患者的选择，防止高风险患者的肝脏浪费， 无效，并确定治疗靶点，以扭转虚弱和改善患者生存。

Project Summary/Abstract DESCRIPTION: This application for a Mentored Clinician Scientist Development Award (K08) is designed to evaluate the effect of cirrhosis-induced immune dysfunction on liver transplant outcomes. The candidate is a transplant surgeon and immunologist whose long-term goal is to develop treatments to prevent immune frailty and improve liver transplant recipient survival. In order to fulfill the educational objectives of this award, this proposal will expand the applicant’s knowledge base into novel lines of translational research inquiry and delve into new areas of investigation requiring focused mentorship. The mentors assisting in the applicant’s development will be crucial for her success, for the performance of the proposed studies, and for the educational mission of the award. Xian Li, PhD, a leader in basic science immunology, and Mark Ghobrial, MD, PhD, a leader in clinical and translational research, will serve as co-mentors. They will be assisted by Drs. Dale Hamilton and Anisha Gupte, who will provide mentorship in bioenergetics; Dr. Ed Graviss, who will provide expertise in biostatistics; Dr. Wenhao Chen, who will provide expertise in T cell exhaustion, and Dr. Todd Eagar, who will provide expertise in inflammation. A rigorous career development plan will be implemented, including structured workshops, biostatistics course work, scientific seminars, and lab meetings. This combination will be instrumental in ensuring the candidate’s successful transition to a career as an independent investigator. PROJECT SUMMARY: Due to organ shortage, livers are transplanted in order of recipient medical urgency; however, ethical principles dictate avoidance of futile transplantation. Due to imbalance in supply and demand for organs, illness severity (categorized by MELD score) has drastically increased. MELD does not correlate well with risk of death post-transplant; thus, better metrics to evaluate risk of mortality are necessary. The most common cause of death early after liver transplant relates to consequences of an immune system which is frail or dysfunctional prior to transplant. In pre-transplant cirrhotics, immune frailty may relate to metabolic deficiencies or T cell exhaustion and may affect liver transplant outcomes. Based on this, it is hypothesized that the pre-transplant state of immunologic frailty results from cirrhosis-related alterations in recipient metabolism, resulting in global T cell metabolic dysfunction, increased T cell exhaustion, and limited adaptive immune proliferation and function. Persistence of immunologic frailty following liver transplant results in increased recipient mortality. This will be addressed by three Aims, which will (1) evaluate metabolic alterations in liver transplant recipients and determine the bioenergetics pathways involved in immune frailty, (2) examine the role of T cell exhaustion in immune frailty, and (3) determine the longitudinal effect of frailty on the recipient post-transplant immune response. IMPACT: These studies are critically important to identify biological markers of immunologic frailty. Defining pre- transplant frailty will improve patient selection for liver transplant, prevent wasting of livers in patients at high risk of futility, and identify therapeutic targets to reverse frailty and improve patient survival.