Role of Kidney-Draining Lymph Node in Crescentic Glomerulonephritis

项目概要/摘要 这份提案详细介绍了以发展平台为中心的五年研究职业发展计划 用于将用于新月体肾小球肾炎（CGN）的免疫抑制剂（ISA）靶向递送至 肾引流淋巴结（KLN），这可以提高疗效，降低电流的毒性 这种情况的标准疗法候选人是哈佛大学医学系的讲师 医学院（HMS）和布里格姆妇女医院肾脏医学部副医师 医院（BWH）。该提案详细说明了候选人通过以下指导实现独立的明确途径： 一个多学科的科学家小组，具有互补的专门知识和模范的指导记录：（1） Reza Abdi（Mentor），BWH的NIH资助的移植肾病学家，拥有2项R 01赠款，（2）大卫萨兰特 （顾问），波士顿大学肾小球疾病领域世界知名的内科医生兼研究者，（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进行药物输送的开创性研究。这一指导将得到以下方面的支持： 追求课程和实验室技能的收购是针对候选人的职业目标， 这对他作为肾免疫学领域的医生-科学家成功过渡到独立至关重要。 CGN的标准治疗，CGN是一种可导致肾衰竭的快速进展性炎症性疾病 在几天内，涉及使用强效全身ISA，可能会导致严重的副作用， 死亡因此，CGN的靶向免疫抑制治疗存在迫切的未满足的临床需求，但 这仍然是一个未充分探索的研究领域。成纤维细胞网状细胞（FRC）是成纤维细胞的常驻基质细胞。 淋巴结（LN），积极促进适应性免疫反应的传播。初步 来自候选人发表的第一作者研究的数据表明，九龙线中FRC的活动是 在称为CGN的小鼠模型中， 肾毒性血清肾炎（NTN）。此外，候选人的实验室已经合成了MECA 79 在NTN期间特异性定位于KLN的抗体缀合的聚合物纳米颗粒（MECA 79-NP）。 该提议的主要目的是确定FRC的活化如何促进促炎性细胞因子的表达。 在CGN期间KLN中的环境，以便确定用于对抗CGN的新治疗策略的新靶点。 本提案的目的是（1）探索采用促炎性药物的机制， （2）研究FRCs在CGN中KLN淋巴管扩张中的作用。 在CGN期间KLN内的脉管系统，和（3）开发一流的纳米制剂， 向九龙铁路公司发出《国际审计准则》，以有效打击中广核。这些研究的结果可以帮助解决紧迫的问题。 CGN治疗中的精准医学的临床需求。

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.