Remote injury responses after AKI

AKI 后的远程损伤反应

• 批准号: 10415933
• 负责人: Andreas Herrlich
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415933
• 关键词: Acute Lung Injury; Acute Renal Failure with Renal Papillary Necrosis; Acute myocardial infarction; Alveolar Macrophages; Bilateral; Blood Circulation; Bone Marrow; Brain; CCL2 gene; Cell surface; Cells; Complication; Creatinine; Cytometry; Data; Development; Gene Expression Profile; Genetic; Goals; Health Expenditures; Heart; Heterogeneity; Human; Immune; Immune response; Inflammation; Inflammatory; Injury; Injury to Kidney; Interleukin-6; Kidney; Knock-out; Knockout Mice; Lead; Lung; Measurement; Mediating; Mediator of activation protein; Metalloproteases; Mission; Molecular; Morbidity - disease rate; Mus; Necrosis; Nephrectomy; Organ; Outcome; Patients; Phenotype; Proliferating; Publishing; Reporting; Research; Respiratory Acidosis; Role; Secondary to; Sepsis; Serum; Signal Transduction; Site; Source; Stains; Stroke; T-Lymphocyte; TNF gene; TNFRSF1A gene; Testing; Time; Tissues; Tubular formation; Tumor Cell Necrosis; Tumor-Derived; Up-Regulation; Urine; Work; cell type; cytokine; improved; in vivo; injured; injury recovery; innovation; interstitial; kidney cell; knockout gene; lung injury; macrophage; monocyte; mortality; mortality risk; neutrophil; novel; novel strategies; novel therapeutics; rat KIM-1 protein; recruit; resilience; response; response to injury; single-cell RNA sequencing; systemic intervention; targeted treatment; therapy development; time use; translational impact; tumor

PROJECT SUMMARY ABSTRACT The overall goal of our research is to develop novel strategies to treat secondary complications of acute kidney injury (AKI). Remote acute lung injury (ALI) is a frequent and often lethal complication of acute kidney injury (AKI) that lacks therapies. Molecular mechanisms of AKI-ALI are incompletely understood, but circulating inflammatory cytokines, e.g. tumor-necrosis-factor (TNF) and T cells have been implicated. Which specific kidney cell types release and which lung cell types or immune cells are targeted by these mediators is unknown. Macrophage accumulation in the lung has been reported in AKI-ALI in mice and human, but whether this occurs by recruitment of bone marrow-derived circulating CCR2+monocytes or proliferation of tissue resident macrophages is unknown. Macrophage responses as well as their heterogeneity are critical determinants of tissue responses to injury. The overall lung remote immune response to AKI and the origin and heterogeneity of lung macrophages in AKI-ALI are unknown. The objective of this application is to determine the role of proximal tubule cell (PTC)- derived TNF and of TNFR1 in lung interstitial macrophages in AKI-ALI, to determine the origin and heterogeneity of kidney/lung macrophages after AKI, and to compare local and remote injury responses in kidney and lung after AKI. Our central hypothesis is (1) PTC-derived TNF is an AKI-ALI mediators and (2) local and remote immune responses share common features but have important differences. Our preliminary work suggests that PTC-derived TNF mediates inflammation and CCR2+-dependent interstitial macrophage recruitment to the lung, and targets lung interstitial macrophages. We detect similarities in local and remote injury responses, but also significant differences, e.g in response of the lung to AKI vs. to acute myocardial infarction. The rationale for this project is that completion will (1) identify PTC-derived TNF as an AKI-ALI mediators, and lung interstitial macrophages as its target cell in the lung, and (2) identify common features and significant differences in local and remote immune responses that could be exploited for targeted therapies. We plan to test our central hypothesis with two specific aims: AIM 1: Determine the role of PTC-derived TNF and of TNFR1 interstitial macrophage knockout in AKI-ALI (using cell type-specific KO mice) AIM 2: Determine the origin of interstitial macrophages in AKI-ALI and their heterogeneity, and compare local kidney immune cell responses to remote lung immune cell responses in AKI-ALI (using fate-mapping and scRNAseq). As outcomes, we expect that TNF- PTC-KO protects against AKI-ALI, and that comparison of local and remote injury responses identifies important differences. This contribution is significant because it is expected to have translational impact in the development of treatments for secondary AKI complications with high mortality, such as AKI-ALI. Our research is innovative, in our opinion, because, it would for the first time identify the source (PTC) and target cells (interstitial macrophages_ of AKI-ALI mediators in the kidney, and for the first time use single cell RNAseq to define local and remote immune responses AKI-ALI.

项目概要摘要 我们研究的总体目标是开发治疗急性肾继发并发症的新策略 损伤（AKI）。远程急性肺损伤 (ALI) 是急性肾损伤 (AKI) 的常见且往往致命的并发症 缺乏治疗方法。 AKI-ALI 的分子机制尚不完全清楚，但循环炎症 细胞因子，例如肿瘤坏死因子 (TNF) 和 T 细胞也参与其中。哪些特定的肾细胞类型 释放以及这些介质针对哪些肺细胞类型或免疫细胞尚不清楚。巨噬细胞 据报道，在小鼠和人类的 AKI-ALI 中，肺部有积聚，但这种情况是否通过募集发生 骨髓来源的循环 CCR2+ 单核细胞或组织驻留巨噬细胞的增殖是 未知。巨噬细胞反应及其异质性是组织反应的关键决定因素 受伤。 AKI 的整体肺远程免疫反应以及肺巨噬细胞的起源和异质性 AKI-ALI 中的情况尚不清楚。本应用的目的是确定近曲小管细胞 (PTC) 的作用 - AKI-ALI 肺间质巨噬细胞中衍生的 TNF 和 TNFR1，以确定来源和异质性 AKI 后肾/肺巨噬细胞的变化，并比较肾和肺的局部和远程损伤反应 AKI 后。我们的中心假设是 (1) PTC 衍生的 TNF 是 AKI-ALI 介质，以及 (2) 本地和远程 免疫反应具有共同特征，但也有重要差异。我们的初步工作表明 PTC 衍生的 TNF 介导炎症和 CCR2+ 依赖性间质巨噬细胞募集至肺部， 并针对肺间质巨噬细胞。我们发现本地和远程伤害反应的相似之处，但也 显着差异，例如肺部对 AKI 的反应与对急性心肌梗死的反应。这样做的理由 该项目的完成将 (1) 确定 PTC 衍生的 TNF 作为 AKI-ALI 介质，以及肺间质 巨噬细胞作为其在肺中的靶细胞，并且（2）识别局部的共同特征和显着差异 以及可用于靶向治疗的远程免疫反应。我们计划测试我们的中央 该假设有两个具体目标： AIM 1：确定 PTC 衍生的 TNF 和 TNFR1 间质的作用 AKI-ALI 中的巨噬细胞敲除（使用细胞类型特异性 KO 小鼠）目标 2：确定间质的起源 AKI-ALI 中的巨噬细胞及其异质性，并比较局部肾脏免疫细胞与远程免疫细胞的反应 AKI-ALI 中的肺免疫细胞反应（使用命运图谱和 scRNAseq）。作为结果，我们预计 TNF- PTC-KO 可预防 AKI-ALI，并且本地和远程损伤反应的比较可以确定重要的 差异。这一贡献意义重大，因为预计它将对开发产生转化影响 死亡率高的继发性 AKI 并发症（例如 AKI-ALI）的治疗方法。我们的研究具有创新性， 我们认为，因为，它将首次识别源细胞（PTC）和目标细胞（间质细胞） 肾脏中 AKI-ALI 介质的巨噬细胞_，并首次使用单细胞 RNAseq 定义局部 和远程免疫反应 AKI-ALI。