Targeting bone marrow to treat renal disease

靶向骨髓治疗肾脏疾病

基本信息

批准号：
10584343
负责人：
Eunsil Hahm
金额：
$ 60.79万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2023-08-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10584343
关键词：
Adult Affect Albumins Biological Assay Blood Cells Bone Marrow Bone Marrow Aspiration Bone Marrow Cells Bone Marrow Transplantation CD14 gene Categories Cell Lineage Cell physiology Chronic Data Development Diagnosis Disease Disease stratification End stage renal failure Exhibits FCGR3B gene Focal and Segmental Glomerulosclerosis Goals Health Hematopoiesis Hematopoietic stem cells Human IL8 gene Immune Immune system Immunologic Factors In Vitro Incidence Individual Inflammation Inflammatory Injury to Kidney Interleukin-6 Kidney Kidney Diseases Kidney Transplantation Macrophage Mediating Modeling Molecular Mus Myelogenous Myeloid Cells Myelopoiesis Nature Nephrotic Syndrome Pathogenesis Pathogenicity Pathway interactions Patients Permeability Phenotype Plasma Production Proteinuria Publishing Recurrence Recurrent disease Remission Induction Renal function Renal glomerular disease Role Signal Transduction Source System Testing Therapeutic Effect Therapeutic immunosuppression Urokinase Plasminogen Activator Receptor Zebrafish candidate identification cytokine effective therapy experience glomerular filtration granulocyte hematopoietic stem cell differentiation humanized mouse improved in vitro Assay in vivo monocyte novel novel therapeutic intervention novel therapeutics patient stratification prevent progenitor side effect targeted treatment

项目摘要

Project Summary/Abstract The goal of this project is to explore a role for the bone marrow (BM) immune system in the pathogenesis of idiopathic nephrotic syndrome (NS) and uncover key immune signatures of the disease. Inflammation and immune system activation have long been considered the major culprits of idiopathic NS, yet the underlying mechanisms are still poorly understood. Primary focal segmental glomerular sclerosis (FSGS) is one of the most common causes of non-familial idiopathic NS in adults. While it is often responsive to immunosuppressive therapy, in many cases patients experience a progressive loss of renal function. Moreover, about 30~50% of FSGS cases recur in newly transplanted kidneys. While its incidence keeps rising, there is no cure for FSGS, and current treatment options are non-specific and often cause significant side effects. Thus, there is an urgent need to identify the immune factors and relevant mechanisms that can be targeted therapeutically to treat idiopathic NS such as FSGS and prevent recurrence of the disease. We recently discovered that BM-derived immature myeloid cells are a main source of circulating soluble urokinase receptor (suPAR) and contribute to proteinuric kidney diseases such as FSGS. These findings suggest that the BM is not simply a place for blood cell production, but is also a central and upstream regulator of kidney function by acting as the source of soluble factors such as suPAR. Consistent with results seen in mice, our preliminary data shows that patients with ESRD have high levels of TNFa and suPAR in both plasma and BM, reflecting a status of chronic inflammation. Moreover, these patients exhibit myeloid-biased hematopoiesis and show a robust increase in inflammatory CD14+CD16+ BM monocytes that are found to predominantly express uPAR. In vitro assays show that TNFa skews hematopoietic stem cell (HSC) differentiation towards monocytic lineage cells at the expense of granulocyte production. Along with the altered myelopoiesis, we found that TNFa markedly increases uPAR expression, suPAR secretion, and promotes production of proinflammatory cytokines including TNFa, IL-8, and IL-6. Based on our published and preliminary data, we hypothesize that inflammatory signals alter BM myelopoiesis leading to renal injury in certain forms of glomerular diseases and that this can be treated or reversed by correcting the inflammation-driven BM alteration. To test this hypothesis, we will precisely define the nature of the BM immune alteration in renal disease (Aim 1), determine how the BM immune factors drive renal injury (Aim 2), and test if BM correction improves renal function (Aim 3). Importantly, the identification of immune factors and relevant mechanisms in patients diagnosed with kidney disease will improve the current stratification of the disease and help to develop novel therapies for certain forms of proteinuric kidney diseases currently categorized as ‘idiopathic’.

项目概要/摘要该项目的目标是探索骨髓（BM）免疫系统在疾病发病机制中的作用特发性肾病综合征 (NS) 并揭示该疾病的关键免疫特征。长期以来，免疫系统激活一直被认为是特发性 NS 的主要原因，但其根本原因是原发性局灶节段性肾小球硬化症（FSGS）是最常见的机制之一。成人非家族性特发性 NS 的常见原因，但通常对免疫抑制有反应。治疗后，许多患者会出现肾功能进行性丧失的情况，而且约30%~50%的患者会出现肾功能逐渐丧失的情况。 FSGS 病例在新移植的肾脏中复发，尽管其发病率不断上升，但 FSGS 无法治愈。目前的治疗方案缺乏特异性，常常会引起明显的副作用，因此，迫切需要解决这一问题。需要确定可以靶向治疗的免疫因子和相关机制特发性 NS 如 FSGS 并预防疾病复发。我们最近发现，骨髓来源的未成熟骨髓细胞是循环可溶性骨髓细胞的主要来源。这些发现表明，尿激酶受体 (suPAR) 会导致 FSGS 等蛋白尿肾病。 BM不仅是血细胞生成的场所，也是肾脏的中枢和上游调节者通过作为可溶性因子（例如 suPAR）的来源发挥功能，我们的研究与在小鼠中观察到的结果一致。初步数据显示，ESRD 患者血浆和 BM 中 TNFa 和 suPAR 水平较高，此外，这些患者表现出骨髓偏向的造血功能和慢性炎症状态。显示炎性 CD14+CD16+ BM 单核细胞的强劲增加，这些单核细胞被发现主要表达 uPAR。体外测定表明 TNFa 使造血干细胞 (HSC) 向单核细胞分化。谱系细胞以牺牲粒细胞生成为代价，伴随着骨髓生成的改变，我们发现 TNFa。显着增加 uPAR 表达、suPAR 分泌，并促进促炎细胞因子的产生包括 TNFa、IL-8 和 IL-6。根据我们已发表的初步数据，我们发现炎症信号会改变 BM 骨髓细胞生成导致某些形式的肾小球疾病的肾损伤，并且可以通过以下方法治疗或逆转：纠正炎症驱动的 BM 改变为了检验这一假设，我们将精确定义 BM 的本质。肾脏疾病中的 BM 免疫改变（目标 1），确定 BM 免疫因素如何驱动肾损伤（目标 2），并测试 BM 校正是否改善肾功能（目标 3）。诊断肾病患者的影响因素和相关机制将改善目前的分层疾病并帮助开发目前某些形式的蛋白尿肾病的新疗法归类为“特发性”。