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: 10229394
• 负责人: Sarah E Panzer
• 金额: $ 16.78万
• 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/10229394
• 关键词: Address; Allografting; Animals; Antibodies; Antibody Formation; Applications Grants; Area; Attenuated; Award; B-Lymphocytes; Biological Markers; Biopsy; Cell Maturation; Cell Survival; Cell Therapy; Cell physiology; 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; Universities; Urine; Wisconsin; Work; antibody-mediated rejection; base; belimumab; biobank; career development; clinically relevant; clinically significant; cohort; cytokine; design; donor-specific antibody; 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; therapeutically effective; therapy development; translational research program; transplant centers; transplant model; transplantation therapy

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.

项目总结/摘要 该提案提出了一个为期四年的职业发展计划，旨在提供莎拉Panzer，医学博士， 美国威斯康星大学麦迪逊分校助理教授，职业发展和研究经历 有必要成为一个独立的医生科学家，以提高患者和移植肾存活率 移植接受者大约50%的移植肾在移植后10年内衰竭。的 移植肾移植失败的主要病理诊断是移植肾小球病（TG）。虽然TG在很大程度上 由于慢性抗体介导的排斥反应（cABMR），该过程的关键介质仍然存在 未知的，没有有效的治疗方法存在。在许多B细胞介导的疾病中，B细胞存活 细胞因子已被证明可加重疾病的活性，并代表了可行的治疗靶点。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。这个建议的假设是B细胞存活的细胞因子发挥作用 在促进TG的发生和预测移植物衰竭中起关键作用。本提案将检验这一点 通过1）在动物肾移植模型中缺乏B细胞细胞因子来减弱TG假设，2） 测定移植物内B细胞因子预测普遍TG患者同种异体移植物衰竭的能力，以及 3)在一项前瞻性观察性研究中确定B细胞存活细胞因子作为甘油三酯事件的危险因素 高风险肾移植患者队列。这些数据将支持未来R 01资助的研究来调查B TG中的细胞生存细胞因子作为治疗靶点。作为一名初级教员， 基础设施，以支持早期阶段的研究人员和一个高度活跃的移植中心，博士Panzer是在一个理想的 环境，以完成拟议的研究和追求先进的培训。她的职业发展计划 包括临床研究设计、主题、临床试验设计、临床试验设计和临床试验设计等领域的课程作业和指导性研究培训。 招聘和保留，以及生存分析。为了确保成功，她已经确定了承诺，专家 导师和安全的保护时间为这项工作。该奖项解决了肾脏领域的重大空白 移植，同时提供指导的研究经验，这对Panzer博士成为一名 成功的内科医生科学家领导一个项目，以改善肾移植的结果。