Role of Kidney-Draining Lymph Node in Crescentic Glomerulonephritis

项目概要/摘要 该提案详细介绍了以开发平台为中心的五年研究职业发展计划 用于针对新月体肾小球肾炎 (CGN) 的免疫抑制剂 (ISA) 的靶向递送 肾引流淋巴结（KLN），可增加疗效并降低目前的毒性 这种情况的标准疗法。该候选人是哈佛大学医学系的讲师 布莱根妇女医院医学院 (HMS) 和肾内科副医师 医院（BWH）。该提案详细说明了候选人通过指导的明确独立之路 一个由具有互补专业知识和模范指导记录的多学科科学家组成的小组：(1) Reza Abdi（导师），BWH 的 NIH 资助肾移植专家，拥有 2 项 R01 资助，(2) David Salant （顾问），波士顿大学肾小球疾病领域世界著名医师研究员，(3) Ulrich von Andrian（顾问），HMS 杰出的淋巴结免疫学家，和 (4) Jeffrey Karp（顾问），工程师 在 HMS 和 BWH 工作，在药物输送方面进行开创性研究。该指南将得到以下方面的支持 追求适合候选人职业目标的课程作业和获得实验室技能， 对于他作为肾脏免疫学领域的医师科学家成功过渡到独立至关重要。 CGN 的标准治疗方法，CGN 是一种快速进展的炎症性疾病，可导致肾衰竭 几天之内，涉及使用强效的全身性 ISA，这可能会导致严重的副作用，从而导致 死亡。因此，针对 CGN 的靶向免疫抑制治疗存在迫切的未满足的临床需求，但 这仍然是一个尚未充分探索的研究领域。成纤维细胞网状细胞 (FRC) 是常驻基质细胞 淋巴结 (LN) 积极促进适应性免疫反应的传播。初步 候选人发表的第一作者研究数据表明 KLN 中 FRC 的活动是 对于 CGN 小鼠模型中细胞介导的免疫反应的传播至关重要 肾毒性血清肾炎（NTN）。此外，该候选人的实验室还合成了MECA79 NTN 期间特异性定位于 KLN 的抗体缀合聚合物纳米颗粒 (MECA79-NP)。 该提案的主要目的是确定 FRC 的激活如何促进促炎 CGN 期间在 KLN 的环境中进行研究，以确定对抗 CGN 的新治疗策略的新靶标。 该提案的目的是（1）探索促炎药物采用的机制 CGN 期间 KLN 中 FRC 的表型，(2) 研究 FRC 在淋巴管扩张中的作用 CGN 期间 KLN 内的脉管系统，以及 (3) 开发一种一流的纳米治疗剂，可提供 向 KLN 发出 ISA，以有效压制 CGN。这些研究的结果可以帮助解决紧迫的问题 临床需要精准医疗治疗 CGN。

Project Summary/Abstract This proposal details a five-year research career development plan centered on the development of a platform for the targeted delivery of immunosuppressive agents (ISAs) for crescentic glomerulonephritis (CGN) to the kidney-draining lymph node (KLN), which can increase the efficacy and reduce the toxicity of the current standard therapy for this condition. The candidate is an Instructor in the Department of Medicine at Harvard Medical School (HMS) and Associate Physician in the Division of Renal Medicine at Brigham and Women's Hospital (BWH). This proposal details a clear path to independence for the candidate through the guidance of a multi-disciplinary group of scientists with complementary expertise and exemplary records of mentorship: (1) Reza Abdi (Mentor), an NIH-funded transplant nephrologist at BWH who holds 2 R01 grants, (2) David Salant (Advisor), a world-renowned physician-investigator in glomerular disease at Boston University, (3) Ulrich von Andrian (Advisor), a preeminent lymph node immunologist at HMS, and (4) Jeffrey Karp (Advisor), an engineer at HMS and BWH who conducts pioneering research in drug delivery. This guidance will be bolstered by pursuit of coursework and acquisition of laboratory skills that are tailored to the candidate's career goals and crucial for his successful transition to independence as a physician-scientist in the field of renal immunology. The standard treatment for CGN, a rapidly progressive inflammatory condition that can lead to kidney failure within days, involves the use of potent systemic ISAs that can cause severe side effects that may result in death. Therefore, a pressing unmet clinical need exists for targeted immunosuppressive therapy for CGN, but this remains an underexplored field of research. Fibroblastic reticular cells (FRCs) are resident stromal cells of the lymph node (LN) that contribute actively to the propagation of an adaptive immune response. Preliminary data from a first-author study published by the candidate indicates that the activity of FRCs in the KLN is crucial to the propagation of the cell-mediated immune response in a mouse model of CGN known as nephrotoxic serum nephritis (NTN). In addition, the candidate's laboratory has synthesized a MECA79 antibody-conjugated polymeric nanoparticle (MECA79-NP) that localizes specifically to the KLN during NTN. The main objective of this proposal is to determine how the activation of FRCs promotes a pro-inflammatory milieu in the KLN during CGN in order to identify new targets for a novel therapeutic strategy to combat CGN. The aims of this proposal are to (1) explore the mechanism governing the adoption of a pro-inflammatory phenotype by FRCs in the KLN during CGN, (2) investigate the role of FRCs in the expansion of the lymphatic vasculature within the KLN during CGN, and (3) develop a first-in-class nanotherapeutic agent that delivers ISAs to the KLN to suppress CGN effectively. The results from these studies could assist in solving the urgent clinical need for precision medicine in the treatment of CGN.