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：
10362747
负责人：
Leyuan Xu
金额：
$ 15.18万
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/10362747
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.

项目摘要/摘要急性肾脏损伤（AKI）显着增加了出现进行性肾纤维化和慢性的风险肾脏疾病（CKD）。巨噬细胞在AKI中起复杂的作用，具有经典的激活促炎巨噬细胞最初用于清除受伤后凋亡细胞和碎屑，并激活促进小管修复的修复性巨噬细胞，然后出口或巨噬细胞凋亡自适应维修的事件。但是，持续的实质炎症或更严重的损伤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）后修复会导致异常的元素内纤维化巨噬细胞和树突状细胞的积累超过第10天。潜在的巨噬细胞寄养和纤维化的表达未修复的肾脏中的激活信号揭示了巨噬细胞趋化剂蛋白1的高级表达（MCP1），主要是巨噬细胞，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。 MCP1，CCR2的同源受体在所有骨骼上都高度表达骨髓衍生的细胞；虽然在两个巨噬细胞上都高度表达了Brp39，CRTH2的纤维纤维化受体和肌纤维细胞。我们发现来自BRP39 - / - 小鼠和CCR2 - / - 小鼠的受伤肾脏表现出较少的纤维化巨噬细胞的积累和间质纤维化比野生型对照小鼠。这些发现在一起我们假设肾脏损伤后的小管修复失败会促进持续的管状细胞表达 BRP39，CRTH2+巨噬细胞增加和肌纤维细胞纤维纤维纤维激活，并且Brp39刺激巨噬细胞上调MCP1，导致进一步的CCR2依赖性促炎细胞积累，肌纤维细胞激活，肾纤维化和功能障碍。因此，针对BRP39-CRTH2和/或MCP1-CCR2 肾脏损伤后的信号通路具有巨大的CKD进展治疗潜力。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中，CCR2+炎性细胞的积累和激活（AIM 1）；和然后确定持续的管状细胞-brp39表达在CRTH2+的纤维化激活中的重要性巨噬细胞和肌纤维细胞（AIM 2）。最后，为了翻译我们对这两个信号的理解在临床上相关的治疗剂的发展中，我们将设计和测试两个不同的基于树枝状聚合物用于选择性靶向近端小管-BRP39表达和间质巨噬细胞CCR2的纳米医学和-CRTH2信号传导对缓慢或防止CKD进展的响应（AIM 3）。研究和职业该K01提案中的开发/培训活动旨在为Leyuan Xu博士提供技术和科学专业知识和成为独立研究人员的经验，探索CKD和它相关的翻译医学。