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

将免疫学衰弱定义为人类同种异体肝脏移植受者无用的预测因子

• 批准号: 10854031
• 负责人: Keri Elizabeth Lunsford
• 金额: $ 14.1万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10854031
• 关键词: Address; Affect; Area; Award; Basic Science; Bioenergetics; Biological Markers; Biometry; Categories; Cause of Death; Cessation of life; Cirrhosis; Development; Development Plans; Disease; Doctor of Philosophy; Education; Educational workshop; Ensure; Ethics; Futility; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Markers; Immunologics; Immunologist; Immunology; Infection; Investigation; Liver; Lymphoproliferative Disorders; Malignant Neoplasms; Medical; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Mission; Organ; Outcome; Pathway interactions; Patient Selection; Patients; Performance; Proliferating; Recurrence; Research Personnel; Role; Scientist; Sepsis; Severity of illness; Structure; T-Lymphocyte; Translational Research; Transplant Recipients; Transplant Surgeon; Transplantation; Transplantation Immunology; Work; career; career development; design; exhaustion; frailty; graft vs host disease; high risk; improved; knowledge base; liver allograft; liver transplantation; meetings; mortality; mortality risk; novel; post-transplant; prevent; research and development; success; therapeutic target; wasting

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.

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。 William Gause博士，基础科学免疫学的领导者，将担任导师。他们将得到博士的帮助。 Xian Li，将提供移植免疫学方面的指导;乔治雅普博士，将提供移植免疫学方面的指导。 王亚群博士，他将提供生物统计学方面的专业知识;和马克·爱因斯坦博士 谁将提供翻译研究和职业发展的专业知识。严格的职业发展计划 将实施，包括结构化的研讨会，生物统计课程工作，科学研讨会，和实验室 会议.这种组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、增加的T细胞耗竭以及有限的适应性免疫增殖和功能。 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。

项目成果

Liver Transplantation for Cholangiocarcinoma: Insights into the Prognosis and the Evolving Indications.

胆管癌肝移植：洞察预后和不断变化的适应症。

• DOI: 10.1007/s11912-020-00910-1
• 发表时间: 2020
• 期刊: Current oncology reports
• 影响因子: 4.7
• 作者: Panayotova,GuerganaG;Paterno,Flavio;Guarrera,JamesV;Lunsford,KeriE
• 通讯作者: Lunsford,KeriE

Gender and Racial Disparity Among Liver Transplantation Professionals: Report of a Global Survey.

• DOI: 10.3389/ti.2022.10506
• 发表时间: 2022
• 期刊: TRANSPLANT INTERNATIONAL
• 影响因子: 3.1
• 作者: Aguilera, Victoria;Andacoglu, Oya;Francoz, Claire;Berlakovich, Gabriela;Pai, Sher-Lu;Adelmann, Dieter;Ghosh, Simantika;Lunsford, Keri E.;Montenovo, Martin;Mrzljak, Anna;Scalera, Irene;Xie, Qinfen;Becchetti, Chiara;Berenguer, Marina;Selzner, Nazia
• 通讯作者: Selzner, Nazia

Expanding indications for liver transplantation in the era of liver transplant oncology.

• DOI: 10.4240/wjgs.v13.i5.392
• 发表时间: 2021-05-27
• 期刊: World journal of gastrointestinal surgery
• 影响因子: 2
• 作者: Panayotova G;Lunsford KE;Latt NL;Paterno F;Guarrera JV;Pyrsopoulos N
• 通讯作者: Pyrsopoulos N

Improving Patient Access to Liver Allografts Through a Mathematically Optimized Continuous Organ Distribution Model.

通过数学优化的连续器官分布模型改善患者获得同种异体肝脏移植的机会。

• DOI: 10.1097/tp.0000000000003018
• 发表时间: 2020
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Panayotova,GuerganaG;Guarrera,JamesV;Lunsford,KeriE
• 通讯作者: Lunsford,KeriE

Racial Disparities in Liver Transplantation for Hepatocellular Carcinoma: Analysis of the National Inpatient Sample From 2007 to 2014.

肝细胞癌肝移植的种族差异：2007 年至 2014 年全国住院患者样本分析。

• DOI: 10.1097/mcg.0000000000001675
• 发表时间: 2023
• 期刊: Journal of clinical gastroenterology
• 影响因子: 2.9
• 作者: Bodek,DanielD;Everwine,MatthewM;Lunsford,KeriE;Okoronkwo,Nneoma;Patel,PavanA;Pyrsopoulos,Nikolaos
• 通讯作者: Pyrsopoulos,Nikolaos