Role of Kidney-Draining Lymph Node in Crescentic Glomerulonephritis

肾引流淋巴结在新月体肾小球肾炎中的作用

• 批准号: 10382338
• 负责人: Vivek Kasinath
• 金额: $ 16.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-04-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382338
• 关键词: Ablation; Adopted; Adoption; Affect; Antibodies; Antigen-Presenting Cells; Binding; Blood Vessels; Boston; CCL19 gene; CCL21 gene; CD4 Positive T Lymphocytes; CDW52 gene; Cell Proliferation; Cells; Cessation of life; Clinical; Clinical Trials; Crescentic Glomerulonephritis; Data; Development; Development Plans; Dialysis procedure; Drug Delivery Systems; Engineering; Extracellular Matrix; Fiber; Funding; Future; Goals; Grant; High Endothelial Venule; Homing; Hospitals; Human; Immune; Immune response; Immune system; Immunologist; Immunology; Immunosuppressive Agents; In Vitro; Infection; Inflammatory; Injury to Kidney; KDR gene; Kidney; Kidney Failure; Laboratories; Lead; Left; Leukocytes; Lymphangiogenesis; Lymphatic; Measures; Medicine; Mentors; Mentorship; Monoclonal Antibodies; Mus; Nephritis; Pathogenesis; Patients; Permeability; Phenotype; Physicians; Polymers; Population; Production; Publishing; Receptor Signaling; Records; Renal glomerular disease; Reperfusion Injury; Research; Research Personnel; Reticular Cell; Role; Scientist; Serum; Signal Pathway; Site; Spleen; Stromal Cells; Surface; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic immunosuppression; Toxic effect; Transplantation; United States National Institutes of Health; Universities; Vascular Endothelial Growth Factors; Woman; adaptive immune response; antibody conjugate; career; career development; cell mediated immune response; chemokine; combat; dosage; draining lymph node; effector T cell; immune activation; improved; inflammatory milieu; insight; instructor; lymph nodes; lymphatic vasculature; lymphatic vessel; lymphotoxin beta receptor; medical schools; mouse model; multidisciplinary; nanoparticle; nanoparticle delivery; nanotherapeutic; nephrotoxicity; new therapeutic target; novel; novel therapeutic intervention; precision medicine; renal damage; scaffold; side effect; skills; standard care; targeted delivery

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.

项目摘要/摘要 这项建议详细说明了以开发平台为中心的五年研究职业发展计划 将治疗新月体肾炎(CGN)的免疫抑制剂(ISA)定向递送至 肾引流淋巴结术(KLN)，可提高疗效，降低毒副反应 这种情况的标准治疗方法。这位候选人是哈佛大学医学系的讲师 布里格姆医学院(HMS)肾内科副主任医师 医院(BWH)。这项提案详细说明了候选人通过以下方式获得独立的明确途径 一个多学科的科学家小组，具有互补的专业知识和模范的指导记录：(1) Reza Abdi(Mentor)，BWH由NIH资助的移植肾病学家，拥有2笔R01赠款，(2)David Salant (Advisor)，世界著名的波士顿大学肾小球疾病内科研究员，(3)Ulrich Von 安德里安(顾问)，HMS杰出的淋巴结免疫学家，(4)杰弗里·卡普(顾问)，工程师 在HMS和BWH进行药物输送方面的开创性研究。这一指导将得到以下支持 根据应聘者的职业目标进行课程学习和实验室技能的获取 对他作为肾脏免疫学领域的内科科学家成功过渡到独立至关重要。 CGN的标准治疗方法，这是一种快速发展的炎症状态，可能导致肾功能衰竭 在几天内，涉及使用有效的全身性ISA，这可能会导致严重的副作用，可能导致 死亡。因此，对cgn的靶向免疫抑制治疗存在着迫切的未得到满足的临床需求，但是 这仍然是一个未被探索的研究领域。成纤维细胞网状细胞(FRC)是一种常驻的基质细胞。 对适应性免疫反应的传播起积极作用的淋巴结节。初步 候选人发表的一项第一作者研究的数据表明，九龙核中FRCs的活动是 在一种被称为CGN的小鼠模型中，对细胞介导的免疫反应的传播至关重要 肾毒性血清性肾炎(NTN)。此外，候选人的实验室已经合成了一种MECA79 抗体结合的聚合物纳米颗粒(MECA79-NP)，在NTN过程中特异性定位于KLN。 这项建议的主要目的是确定FRC的激活如何促进促炎作用 旨在为对抗CGN的新治疗策略确定新的靶点。 这项建议的目的是(1)探索管理采用促炎措施的机制 慢性肾小球肾炎中FRCs的表型，(2)探讨FRCs在淋巴扩张中的作用 在CGN期间KLN内的血管形成，以及(3)开发一流的纳米治疗剂，可提供 伊萨斯能有效抑制肾小球肾炎。这些研究的结果可能有助于解决紧迫的 临床需要精准医学治疗慢性肾炎。