The Role of the IL-1 Receptor in the AKI to CKD transition

IL-1 受体在 AKI 向 CKD 转变中的作用

基本信息

批准号：
10605321
负责人：
Jamie R Privratsky
金额：
$ 15.81万
依托单位：
DUKE 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：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10605321
关键词：
Acceleration Acute Acute Renal Failure with Renal Papillary Necrosis Admission activity Animal Model Anti-Inflammatory Agents Applications Grants Area Attenuated Behavior Binding CD4 Positive T Lymphocytes Cell Communication Cell Death Cell Surface Receptors Cell physiology Cell surface Cells Chronic Chronic Kidney Failure Coculture Techniques Complex Complication Critical Care Critical Illness Cytometry Death Rate Dendritic Cells Development Fibrosis Foundations Functional disorder Future Gene Activation Gene Expression Goals Health Health Care Costs Human Immune Immune signaling Immune system In Vitro Inflammatory Injury Injury to Kidney Innate Immune Response Interleukin Activation Interleukin-1 Receptors Interleukins Ischemia Kidney Knowledge Leukocytes Life Lymphocyte Lymphocyte Activation Macrophage Measures Mediating Mediator Medicine Methods Mission Modeling Morbidity - disease rate Multiple Organ Failure Mus Myeloid Cells Nature Operative Surgical Procedures Organ Organ failure Organism Patients Phenotype Play Population Process Production Public Health Quality of life Receptor Activation Receptor Signaling Recovery Regulatory T-Lymphocyte Reperfusion Therapy Research Research Personnel Role Sepsis Severities Signal Transduction Sorting Spatial Distribution Syndrome T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TNF gene Techniques Testing Therapeutic Tissues Toxin Training Tubular formation United States National Institutes of Health Ureteral obstruction Work adaptive immune response body system cell injury cell motility cytokine disability draining lymph node experience healing immunomodulatory therapies immunoregulation improved kidney cell kidney fibrosis lymph nodes migration mortality next generation sequencing novel novel imaging technique organ repair prevent programs renal damage repaired septic single-cell RNA sequencing therapy design tissue injury

项目摘要

ABSTRACT Multi-organ dysfunction syndrome (MODS) leads to significant morbidity and mortality in critically ill patients. Acute kidney injury (AKI) is one of the most common components of MODS. Unresolved AKI leads to ongoing renal injury, fibrosis, and subsequent chronic kidney disease (CKD). However, the mechanisms that direct renal recovery and prevent the AKI to CKD transition are poorly understood. One novel and promising therapeutic approach is to modulate the functions of macrophages and dendritic cells (DCs) that accumulate in the injured kidney in order to prevent further injury and fibrosis. Interleukin (IL)-1α/β are canonical pro-inflammatory cytokines that activate macrophages and DCs after binding to their cell surface receptor, IL-1R1. IL-1R1 activation plays a prominent role in renal healing. However, IL-1R1’s specific effects on macrophage and DC function following AKI and on the AKI to CKD transition are poorly understood. Based on our preliminary studies, our central hypothesis is that following AKI, macrophage IL-1R1 activation triggers TNFα (TNF)-dependent renal cell necroptosis, which directs IL-1R1-dependent migration of DCs to lymph nodes to activate pro-inflammatory T cells to drive the AKI to CKD transition. We will test our central hypothesis as follows: Specific Aim 1: Determine effects of macrophage IL-1R1 activation on TNF-mediated renal cell necroptosis following ischemic AKI. Mice with macrophage-specific deletion of IL-1R1 (IL-1R1 MKO) and controls (IL-1R1 MWT) will undergo ischemia/reperfusion (I/R)- and septic AKI, and the severity of acute kidney damage will be quantified. Renal cell necroptosis will be measured in injured kidneys and in macrophage-renal tubular cell (RTC) co-culture. We will employ cell surface phenotyping and single cell RNA-seq on sorted leukocytes from injured kidneys to precisely phenotype myeloid cells to determine how IL-1R1 activation modulates macrophage polarization and renal injury. Specific Aim 2: Elucidate the role of IL-1R1-mediated dendritic cell migration and T cell activation during the AKI to CKD transition. Mice with deletion of IL-1R1 in DCs (IL-1R1 DCKO) and controls (IL-1R1 DCWT) will be subjected to I/R-induced AKI, and at multiple timepoints, the severity of renal damage and fibrosis will be compared. We will examine IL-1R1-mediated accumulation of DC subsets in renal lymph nodes following I/R and their consequent activation of effector lymphocytes. We will use novel tissue cytometry to analyze spatial distribution of DC and T cells within fibrotic areas. Activated DC and T cells will be co-cultured with RTC to determine their effect on pro-fibrotic gene expression programs. The proposed studies will have a significant positive impact by promoting the development of future targeted treatments for patients with life-threatening AKI. Together with my training plan, these studies will lay the foundation for my development as an independent investigator in critical care medicine focused on identifying treatments that promote renal healing after AKI to prevent CKD and remote organ failure.

抽象的多器官功能障碍综合征（MODS）导致重症患者的发病率和死亡率显着。急性肾脏损伤（AKI）是MOD最常见的组成部分之一。未解决的AKI导致肾脏损伤，纤维化和随后的慢性肾脏疾病（CKD）。但是，直接肾脏的机制恢复并防止AKI到CKD过渡的理解很少。一种小说和有前途的疗法方法是调节积聚在受伤的巨噬细胞和树突状细胞（DC）的功能肾脏以防止进一步的损伤和纤维化。白介素（IL）-1α/β是典型的促炎与细胞表面受体IL-1R1结合后激活巨噬细胞和DC的细胞因子。 IL-1R1 激活在肾脏愈合中起着重要的作用。但是，IL-1R1对巨噬细胞和直流的特定影响众所周知，AKI和AKI到CKD转换的功能知之甚少。基于我们的初步研究我们的中心假设是，遵循AKI，巨噬细胞IL-1R1激活触发TNFα（TNF）依赖性肾脏细胞坏死作用，它指导DC依赖IL-1R1依赖性迁移到淋巴结以激活促炎性 T细胞将AKI驱动到CKD转变。我们将测试中心假设，如下：特定目标1：确定巨噬细胞IL-1R1激活对TNF介导的肾细胞的影响缺血性AKI后坏死性。 IL-1R1（IL-1R1 MKO）的巨噬细胞特异性缺失的小鼠和对照（IL-1R1 MWT）将经历缺血/再灌注（I/R）和化粪池AKI，以及急性的严重程度肾脏损伤将被量化。肾细胞坏死性将在受伤的孩子和巨噬细胞 - 肾结核细胞（RTC）共培养。我们将采用细胞表面表型和单细胞从受伤的孩子到精确表型髓样细胞的排序白细胞上的RNA-Seq，以确定如何 IL-1R1激活调节巨噬细胞极化和肾损伤。特定目标2：阐明IL-1R1介导的树突状细胞迁移和T细胞活化的作用在AKI到CKD过渡期间。 DCS（IL-1R1 DCKO）和对照组中删除IL-1R1的小鼠（IL-1R1） DCWT）将受到I/R诱导的AKI，在多个时间点，肾脏损坏的严重程度和将比较纤维化。我们将检查IL-1R1介导的DC子集在肾淋巴中的积累 I/R之后的节点及其随之而来的效应淋巴细胞激活。我们将使用新型组织细胞仪分析纤维化区域内直流和T细胞的空间分布。激活的直流和T细胞将与RTC共同培养，以确定其对促纤维化基因表达程序的影响。拟议的研究将通过促进未来目标的发展产生重大的积极影响对威胁生命的AKI患者的治疗。与我的培训计划一起，这些研究将为我作为重症监护医学独立研究者发展的基础，专注于识别在AKI之后促进肾脏愈合的治疗方法可防止CKD和远程器官衰竭。