Targeting macrophage persistence to prevent the AKI-to-CKD transition

靶向巨噬细胞持久性以防止 AKI 向 CKD 的转变

基本信息

批准号：
9918895
负责人：
Leyuan Xu
金额：
$ 12.07万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918895
关键词：
Acute Renal Failure with Renal Papillary Necrosis Apoptosis Apoptotic Bone Marrow CHI3L1 gene Cell Surface Proteins Cells Cessation of life Chemotactic Factors Chronic Kidney Failure Clinical Research Complex Contralateral Data Dendrimers Dendritic Cells Development Disease Disease Progression Down-Regulation Drug Delivery Systems Drug Kinetics Drug Targeting Engineering Event Exhibits Failure Fibrosis Folic Acid Functional disorder Genes Homing In Vitro Inflammation Inflammatory Injury Injury to Kidney Kidney Kinetics Modeling Mus Myofibroblast Organ Patients Pharmaceutical Preparations Phenotype Play Proteins Proximal Kidney Tubules Publications Publishing Renal function Reperfusion Injury Reporting Research Personnel Risk Role Signal Pathway Signal Transduction T-Lymphocyte Testing Therapeutic Therapeutic Uses Training Activity Transgenic Mice Translating Tubular formation base career development cell type chronic infection clinical development clinically relevant design experience folate-binding protein functional improvement in vivo injured innovation interest interstitial kidney cell kidney dysfunction kidney fibrosis kidney repair macrophage mannose receptor mouse model nanomedicine prevent receptor recruit repaired response severe injury siRNA delivery targeted delivery targeted treatment therapeutic target translational medicine uptake

项目摘要

Project Summary/Abstract Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic kidney disease (CKD). Macrophages play complex roles in AKI, with classically activated proinflammatory macrophages initially serving for clearance of apoptotic cells and debris after injury, and alternatively activated reparative macrophages promoting tubule repair followed by either egress or apoptosis of the macrophages in the event of adaptive repair. However, persistent parenchymal inflammation or more severe injury leads to maladaptive kidney repair. Our recent publication and preliminary data has shown that failure to achieve tubular repair after unilateral ischemia/reperfusion injury (U-IRI) leads to abnormal intrarenal profibrotic macrophage and dendritic cell accumulation beyond day 10. The expression of potential macrophage homing and profibrotic activation signals in unrepaired kidneys reveals high-level expression of macrophage chemoattractant protein-1 (Mcp1), predominantly by macrophages, along with sustained expression of chitinase 3-like 1 (Chi3l1 or Brp39), predominantly by endogenous renal cells. The cognate receptor for Mcp1, Ccr2, is highly expressed on all bone marrow-derived cells; while the profibrotic receptor for Brp39, Crth2, is highly expressed on both macrophages and myofibroblasts. We found that injured kidneys from Brp39-/- mice and Ccr2-/- mice exhibit less profibrotic macrophage accumulation and interstitial fibrosis than wild-type control mice. Together, these findings have led us to hypothesize that failed tubule repair following kidney injury promotes sustained tubular cell expression of Brp39, with increased Crth2+ macrophage and myofibroblast profibrotic activation, and that the Brp39-stimulated macrophages upregulate Mcp1, leading to further Ccr2-dependent proinflammatory cell accumulation, myofibroblast activation, renal fibrosis and dysfunction. Thus, targeting the Brp39-Crth2 and/or Mcp1-Ccr2 signaling pathways after kidney injury holds great potential for the treatment of CKD progression. To test this hypothesis, we propose to first define the role of macrophage-Mcp1 expression in promoting abnormal accumulation and activation of Ccr2+ inflammatory cells in the setting of maladaptive kidney repair (Aim 1); and then determine the importance of sustained tubular cell-Brp39 expression in the profibrotic activation of Crth2+ macrophages and myofibroblasts (Aim 2). Lastly, in order to translate our understanding of these two signaling into the development of clinically relevant therapeutics, we will engineer and test two distinct dendrimer-based nanomedicines for selective targeting of proximal tubule-Brp39 expression and of interstitial macrophage-Ccr2 and -Crth2 signaling responses to slow or prevent CKD progression (Aim 3). The studies and career development/training activities in this K01 proposal are designed to equip Dr. Leyuan Xu with the technical and scientific expertise and the experience to become an independent investigator exploring the topics of CKD and its related translational medicine.

项目概要/摘要急性肾损伤（AKI）显着增加发生进行性肾纤维化和慢性肾纤维化的风险肾脏疾病（CKD）。巨噬细胞在 AKI 中发挥着复杂的作用，具有经典激活的促炎作用巨噬细胞最初用于清除损伤后的凋亡细胞和碎片，然后被激活修复性巨噬细胞促进肾小管修复，随后巨噬细胞流出或凋亡适应性修复的事件。然而，持续的实质炎症或更严重的损伤会导致适应不良的肾脏修复。我们最近的出版物和初步数据表明，未能实现管状单侧缺血/再灌注损伤（U-IRI）后的修复导致肾内促纤维化巨噬细胞异常第 10 天后树突状细胞积聚。潜在巨噬细胞归巢和促纤维化的表达未修复肾脏中的激活信号揭示巨噬细胞趋化蛋白-1的高水平表达 (Mcp1)，主要由巨噬细胞，以及几丁质酶 3 样 1（Chi3l1 或 Brp39）的持续表达，主要由内源性肾细胞产生。 Mcp1 的同源受体 Ccr2 在所有骨骼中高度表达骨髓来源的细胞；而 Brp39 的促纤维化受体 Crth2 在两种巨噬细胞上均高度表达和肌成纤维细胞。我们发现 Brp39-/- 小鼠和 Ccr2-/- 小鼠的受损肾脏表现出较少的促纤维化巨噬细胞积聚和间质纤维化优于野生型对照小鼠。这些发现共同导致我们假设肾损伤后肾小管修复失败会促进肾小管细胞持续表达 Brp39，增加 Crth2+ 巨噬细胞和肌成纤维细胞促纤维化激活，并且 Brp39 刺激巨噬细胞上调 Mcp1，导致 Ccr2 依赖性促炎细胞进一步积累，肌成纤维细胞活化、肾纤维化和功能障碍。因此，针对 Brp39-Crth2 和/或 Mcp1-Ccr2 肾损伤后的信号通路对于治疗 CKD 进展具有巨大潜力。为了测试这个假设，我们建议首先定义巨噬细胞-Mcp1表达在促进异常中的作用在适应不良的肾脏修复过程中 Ccr2+ 炎症细胞的积累和激活（目标 1）；和然后确定肾小管细胞 Brp39 持续表达在 Crth2+ 促纤维化激活中的重要性巨噬细胞和肌成纤维细胞（目标 2）。最后，为了翻译我们对这两个信号的理解为了开发临床相关疗法，我们将设计和测试两种不同的基于树枝状聚合物的用于选择性靶向近曲小管 Brp39 表达和间质巨噬细胞 Ccr2 的纳米药物 -Crth2 信号传导反应可减缓或预防 CKD 进展（目标 3）。学业和职业本 K01 提案中的开发/培训活动旨在使徐乐源博士具备技术和成为探索 CKD 主题的独立研究者的科学专业知识和经验其相关的转化医学。