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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：
10132742
负责人：
Jamie R Privratsky
金额：
$ 18.79万
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/10132742
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis 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-1 Receptors Interleukins Ischemia Kidney Knowledge Leukocytes Life Lymphocyte Lymphocyte Activation Measures Mediating Mediator of activation protein 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 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 base body system cell injury cell motility cytokine disability draining lymph node experience healing immunomodulatory therapies immunoregulation improved kidney cell kidney fibrosis lymph nodes macrophage migration mortality next generation sequencing novel novel imaging technique 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.

摘要多器官功能障碍综合征（MODS）是危重病患者的重要并发症。急性肾损伤（阿基）是MODS最常见的组成部分之一。未解决的阿基导致持续肾损伤、纤维化和随后的慢性肾病（CKD）。然而，肾脏的直接作用机制然而，对AKI的恢复和防止阿基向CKD转变的机制知之甚少。一种新颖而有前途的治疗方法一种方法是调节巨噬细胞和树突状细胞（DC）的功能，这些细胞在损伤的组织中聚集。以防止进一步的损伤和纤维化。白细胞介素（IL）-1α/β是典型的促炎因子，细胞因子在与巨噬细胞和DC的细胞表面受体IL-1 R1结合后激活巨噬细胞和DC。IL-1R1 活化在肾愈合中起着显著的作用。然而，IL-1 R1对巨噬细胞和DC的特异性作用对阿基后以及阿基向CKD转变的功能了解甚少。根据我们的初步研究，我们的中心假设是，阿基后，巨噬细胞IL-1 R1激活触发TNFα（TNF）依赖性肾损伤，细胞坏死性凋亡，其指导DC的IL-1 R1依赖性迁移至淋巴结以激活促炎性细胞因子。 T细胞驱动阿基向CKD转变。我们将测试我们的中心假设如下：具体目的1：确定巨噬细胞IL-1 R1活化对TNF介导的肾细胞的影响缺血性阿基后的坏死性凋亡。巨噬细胞特异性缺失IL-1 R1（IL-1 R1 MKO）的小鼠，对照组（IL-1 R1 MWT）将经历缺血/再灌注（I/R）-和脓毒性阿基，并且急性AKI的严重程度肾脏损伤将被量化。肾细胞坏死将在损伤的肾脏中测量，巨噬细胞-肾小管细胞（RTC）共培养。我们将采用细胞表面表型和单细胞 RNA-seq对从受损肾脏中分选的白细胞进行精确表型骨髓细胞，以确定 IL-1 R1激活调节巨噬细胞极化和肾损伤。具体目标2：阐明IL-1 R1介导的树突状细胞迁移和T细胞活化的作用在阿基向CKD过渡期间。DC中IL-1 R1缺失的小鼠（IL-1 R1 DCKO）和对照小鼠（IL-1 R1 DCWT）将经受I/R诱导的阿基，并且在多个时间点，将比较纤维化。我们将研究IL-1 R1介导的DC亚群在肾淋巴中的积聚， I/R后的淋巴结及其随后的效应淋巴细胞活化。我们将使用新型组织细胞术分析纤维化区域内DC和T细胞的空间分布。活化的DC和T细胞将与RTC共培养以确定它们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有针对性的发展产生重大的积极影响。治疗危及生命的阿基患者。加上我的培训计划，这些研究将奠定作为一名独立的重症监护医学研究者，我的发展基础是，促进阿基后肾脏愈合的治疗，以预防CKD和远端器官衰竭。