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

项目摘要/摘要 描述：本申请导师临床医生科学家发展奖(K08)旨在 评估肝硬变所致免疫功能障碍对肝移植结果的影响。候选人是一位 移植外科医生和免疫学家，他的长期目标是开发预防免疫脆弱和 提高肝移植受者存活率。为了实现该奖项的教育目标，本提案 将把申请者的知识库扩展到翻译研究的新领域，并深入研究新的 需要重点指导的调查领域。帮助申请者发展的导师将是 对她的成功、对拟议研究的表现以及该奖项的教育使命至关重要。 基础科学免疫学领域的领军人物威廉·高斯博士将担任导师。他们将得到Dr。 李先贤将提供移植免疫学方面的指导；George Yap博士将提供 疲惫和生物能量学；王亚群博士，他将提供生物统计学方面的专业知识；以及马克·爱因斯坦博士 世卫组织将提供翻译研究和职业发展方面的专业知识。严谨的职业发展计划 将实施，包括结构化讲习班、生物统计学课程工作、科学研讨会和实验室 开会。这种结合将有助于确保候选人成功过渡到职业生涯 独立调查员。 项目概述：因器官短缺，按受者医疗急症顺序进行肝脏移植； 然而，伦理原则规定了避免徒劳的移植。由于供需不平衡， 器官、疾病严重程度(按MELD评分分类)大幅增加。MELD不能很好地与 移植后死亡风险；因此，有必要采用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 移植前出现功能障碍。在移植前的肝硬变患者中，免疫脆弱可能与代谢缺陷或 T细胞耗尽，并可能影响肝脏移植的结果。在此基础上，假设移植前 免疫脆弱状态是由于与肝硬变相关的受体代谢改变所致，导致全球T细胞 细胞代谢功能障碍，T细胞耗竭增加，适应性免疫增殖和功能受限。 肝移植后持续的免疫脆弱会导致受体死亡率的增加。这将是 由三个目标解决，这将(1)评估肝移植受者的代谢变化并确定 涉及免疫脆弱的生物能量学途径，(2)检测T细胞耗竭在免疫脆弱中的作用， 以及(3)确定脆弱对受者移植后免疫反应的纵向影响。 影响：这些研究对于确定免疫脆弱的生物标志物至关重要。定义Pre- 移植的脆弱性将改善肝移植患者的选择，防止高危患者的肝脏浪费。 徒劳无益，并确定治疗靶点，以扭转虚弱和提高患者存活率。

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. William Gause, PhD, a leader in basic science immunology, will serve as mentors. They will be assisted by Dr. Xian Li, who will provide mentorship in transplant immunology; Dr. George Yap, who will provide mentorship in exhaustion and bioenergetics; Dr. Yaqun Wang, who will provide expertise in biostatistics;, and Dr. Mark Einstein who will provide expertise in translational research and career development. 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.