Improving long-term allograft survival in kidney transplantation by targeting B cell survival cytokines

通过靶向 B 细胞存活细胞因子提高肾移植中的长期同种异体移植物存活率

• 批准号: 9805838
• 负责人: Sarah E Panzer
• 金额: $ 16.93万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9805838
• 关键词: Address; Allografting; Animals; Antibodies; Antibody Formation; Applications Grants; Area; Attenuated; Award; B-Lymphocytes; Biological Markers; Biopsy; Cell Maturation; Cell Survival; Cell physiology; Cells; Chronic; Clinical Research; Clinical Trials; Clinical and Translational Science Awards; Data; Databases; Development; Development Plans; Diagnosis; Diagnostic; Dialysis procedure; Disease; Ensure; Environment; Faculty; Failure; Funding; Future; Goals; Health Care Costs; Immunologics; Incidence; Infrastructure; Injury; Institution; Kidney; Kidney Transplantation; Ligands; Lupus; Mature B-Lymphocyte; Mediating; Mediator of activation protein; Mentors; Mus; Nephrology; Outcome; Pathologic; Pathology; Patient observation; Patients; Physicians; Play; Population; Process; Program Development; Prospective cohort; Rattus; Renal function; Research; Research Design; Research Personnel; Research Training; Resources; Risk Factors; Role; Scientist; Secure; Serum; Severities; Survival Analysis; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; Training; Transplant Recipients; Transplantation; Treatment Efficacy; Universities; Urine; Wisconsin; Work; base; belimumab; biobank; career development; clinically relevant; clinically significant; cohort; cytokine; design; effective therapy; experience; high risk; humoral immunity deficiency; improved; improved outcome; kidney allograft; member; prevent; professor; programs; prospective; recruit; research and development; sample collection; success; therapeutic evaluation; therapeutic target; therapy development; translational research program; transplant centers; transplant model

PROJECT SUMMARY/ABSTRACT The proposal presents a four-year career development program designed to provide Sarah Panzer, MD, an Assistant Professor at the University of Wisconsin-Madison, the career development and research experiences necessary to become an independent physician scientist to improve patient and allograft survival of kidney transplant recipients. Approximately 50% of transplanted kidneys fail within 10 years of transplantation. The major pathologic diagnosis in failing kidney allografts is transplant glomerulopathy (TG). While TG has largely been attributed to chronic antibody-mediated rejection (cABMR), the key mediators of this process remain unknown and no effective therapeutics exist. In a multitude of B cell mediated diseases, the B cell survival cytokines have been demonstrated to exacerbate disease activity and represent a viable therapeutic target. In kidney transplantation, preliminary studies have found elevated levels of B cell survival cytokines in the serum and kidney tissue of patients with cABMR. The hypothesis of this proposal is B cell survival cytokines play pivotal roles in promoting the development of TG and predict allograft failure. This proposal will test this hypothesis via 1) deficiency of B cell cytokines in an animal kidney transplant model to attenuate TG, 2) determination of the ability of intragraft B cell cytokines to predict allograft failure in prevalent TG patients, and 3) determination of B cell survival cytokines as a risk factor for incident TG in a prospective observational cohort of high-risk kidney transplant patients. These data will support future R01 funded study to investigate B cell survival cytokines in TG as a therapeutic target. As a junior faculty member at an institution with extensive infrastructure to support early stage investigators and a highly active transplant center, Dr. Panzer is in an ideal environment to complete the proposed research and pursue advanced training. Her career development plan includes both coursework and mentored research training in the areas of clinical study design, subject recruitment and retention, and survival analysis. To ensure success, she has identified committed, expert mentors and secured protected time for this work. This award addresses a significant gap in the field of kidney transplantation while affording the mentored research experience critical for Dr. Panzer to become a successful physician scientist leading a program to improve outcomes in kidney transplantation.

项目概要/摘要 该提案提出了一项为期四年的职业发展计划，旨在为医学博士 Sarah Panzer 提供一个 威斯康星大学麦迪逊分校助理教授职业发展和研究经历 有必要成为一名独立的医师科学家，以提高患者和同种异体肾脏移植的存活率 移植受者。大约 50% 的移植肾在移植后 10 年内衰竭。这 同种异体肾移植失败的主要病理诊断是移植肾小球病（TG）。虽然 TG 很大程度上 归因于慢性抗体介导的排斥反应（cABMR），这一过程的关键介质仍然存在 未知且不存在有效的治疗方法。在多种 B 细胞介导的疾病中，B 细胞存活 细胞因子已被证明会加剧疾病活动并成为可行的治疗靶点。在 肾移植后，初步研究发现血清中B细胞存活细胞因子水平升高 和 cABMR 患者的肾组织。该提案的假设是B细胞存活细胞因子发挥作用 在促进 TG 的发展和预测同种异体移植失败方面发挥着关键作用。本提案将对此进行测试 通过 1) 动物肾移植模型中 B 细胞细胞因子的缺乏来减弱 TG 的假设，2) 确定移植物内 B 细胞细胞因子预测普遍 TG 患者同种异体移植失败的能力，以及 3) 在前瞻性观察中确定 B 细胞存活细胞因子作为 TG 事件的危险因素 高危肾移植患者队列。这些数据将支持未来 R01 资助的研究来调查 B TG中的细胞存活细胞因子作为治疗靶点。作为一个拥有广泛知识的机构的初级教员 Panzer 博士拥有支持早期研究人员的基础设施和高度活跃的移植中心，处于理想的状态 环境来完成拟议的研究并进行高级培训。她的职业发展规划 包括临床研究设计、主题领域的课程作业和指导研究培训 招募和保留以及生存分析。为了确保成功，她找到了忠诚的专家 导师并为这项工作争取了受保护的时间。该奖项填补了肾脏领域的重大空白 移植，同时提供指导研究经验，这对于 Panzer 博士成为一名 成功的医师科学家领导了一项改善肾移植结果的计划。