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: 10334522
• 负责人: Keri Elizabeth Lunsford
• 金额: $ 18.8万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334522
• 关键词: Address; Affect; Amino Acids; Area; Award; Basic Science; Bioenergetics; Biological Assay; Biological Markers; Biometry; CD8-Positive T-Lymphocytes; Catabolism; Cause of Death; Cell physiology; Cells; Cessation of life; Cirrhosis; Clinical; Clinical Research; Clonality; Delayed Hypersensitivity; Development; Development Plans; Doctor of Philosophy; Educational workshop; Ensure; Eotaxin; Ethics; Evolution; Exhibits; Flow Cytometry; Fractalkine; Futility; Gene Expression; Glucose; Glycolysis; Goals; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunocompetence; Immunologic Markers; Immunologics; Immunologist; Immunology; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; Investigation; Link; Liver; Lymphopenia; Lymphoproliferative Disorders; Malignant Neoplasms; Malnutrition; Medical; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Micronutrients; Mission; Modeling; Muscular Atrophy; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patient Selection; Patients; Performance; Phenotype; Physiological; Production; Proteins; Public Health; Recurrence; Regulatory T-Lymphocyte; Research Personnel; Risk; Risk Factors; Role; Scientist; Sepsis; Serum; Severity of illness; Stromelysin 1; Structure; System; T cell anergy; T-Cell Receptor Genes; T-Lymphocyte; T-Lymphocyte Subsets; T-cell diversity; Testing; Translational Research; Transplant Recipients; Transplant Surgeon; Transplantation; Trauma; United States; Waiting Lists; Work; base; career; career development; chemokine; cytokine; design; end stage liver disease; exhaust; exhaustion; fat wasting; frailty; glucose metabolism; graft vs host disease; high risk; improved; indexing; ketogenesis; knowledge base; lipid metabolism; liver allograft; liver transplantation; meetings; memory CD4 T lymphocyte; metabolic profile; mortality; mortality risk; novel; peripheral blood; post-transplant; prevent; sarcopenia; success; therapeutic target; tumor progression; 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. 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.

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。 李贤博士，基础科学免疫学的领导者，Mark Ghobrial，医学博士，临床和免疫领域的领导者 翻译研究，将担任共同导师。他们将由戴尔·汉密尔顿博士和阿尼莎·古普特博士协助， 世卫组织将提供生物能量学方面的指导；Ed Graviss博士将提供生物统计学方面的专业知识； 陈文浩，他将提供T细胞衰竭方面的专业知识，托德·伊格尔博士，他将提供 发炎。将实施严格的职业发展计划，包括有组织的讲习班， 生物统计学课程工作、科学研讨会和实验室会议。这一组合将有助于确保 候选人成功地过渡到独立调查员的职业生涯。 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。