Targeting bone marrow to treat renal disease

项目总结/摘要 本项目的目标是探索骨髓（BM）免疫系统在骨髓炎发病机制中的作用。 特发性肾病综合征（NS）和揭示疾病的关键免疫特征。炎症和 免疫系统激活长期以来被认为是特发性NS的主要罪魁祸首，然而， 机制仍然知之甚少。原发性局灶节段性肾小球硬化症（FSGS）是最常见的肾小球硬化症之一。 成人非家族性特发性NS的常见原因。虽然它通常对免疫抑制剂有反应， 在治疗中，在许多情况下，患者经历肾功能的进行性丧失。此外，约30~50%的 FSGS病例在新移植肾中复发。虽然其发病率不断上升，但FSGS没有治愈方法， 并且目前的治疗选择是非特异性的，并且经常引起显著的副作用。因此，迫切需要 需要确定免疫因素和相关机制，可以有针对性地治疗， 特发性NS，如FSGS，并防止疾病复发。 我们最近发现，骨髓来源的未成熟髓系细胞是循环可溶性造血干细胞的主要来源。 尿激酶受体（suPAR），并有助于蛋白尿肾病，如FSGS。这些发现表明 BM不仅是血细胞产生的地方，而且是肾脏的中央和上游调节器， 通过作为可溶性因子如suPAR的来源起作用。与在小鼠中观察到的结果一致， 初步数据显示ESRD患者在血浆和BM中具有高水平的TNF α和suPAR， 反映了慢性炎症的状态。此外，这些患者表现出骨髓偏向性造血， 显示炎性CD 14 + CD 16 + BM单核细胞的显著增加， uPAR。体外测定显示TNF α使造血干细胞（HSC）分化偏向单核细胞分化。 谱系细胞，以粒细胞产生为代价。沿着骨髓生成的改变，我们发现TNF α 显著增加uPAR表达，suPAR分泌，并促进促炎细胞因子的产生 包括TNF α、IL-8和IL-6。 基于我们已发表的和初步的数据，我们假设炎症信号改变BM骨髓生成， 在某些形式的肾小球疾病中导致肾损伤，这可以通过以下方法治疗或逆转： 纠正炎症驱动的BM改变。为了验证这一假设，我们将精确地定义 肾脏疾病中的BM免疫改变（目标1），确定BM免疫因子如何驱动肾损伤 (Aim 2），并测试BM校正是否改善肾功能（目的3）。重要的是，免疫识别 诊断为肾脏疾病的患者的因素和相关机制将改善当前的分层 并帮助开发目前某些形式的蛋白尿肾病的新疗法 被归类为“特发性疾病”

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’.