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.

项目摘要摘要 我们研究的总体目标是制定新的策略来治疗急性肾脏的次要并发症 受伤（AKI）。远程急性肺损伤（ALI）是急性肾脏损伤（AKI）的常见且常常致命的并发症 缺乏疗法。 Aki-Ali的分子机制尚不完全了解，但循环炎症 细胞因子，例如肿瘤 - 疾病因素（TNF）和T细胞已与肿瘤不良因素（TNF）。哪种特定的肾细胞类型 这些介体的释放和哪种肺细胞类型或免疫细胞是靶向的。巨噬细胞 在小鼠和人类的Aki-Ali中，肺中的积累已报告，但是是否通过招募发生这种情况 骨髓衍生的循环CCR2+单核细胞或组织驻留巨噬细胞的增殖是 未知。巨噬细胞反应以及它们的异质性是组织反应的关键决定因素 受伤。对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 在Aki-Ali中是未知的。该应用的目的是确定近端小管细胞（PTC） - Aki-Ali的肺间质性巨噬细胞中的TNF和TNFR1的衍生tnf和TNFR1，以确定起源和异质性 AKI之后的肾脏/肺巨噬细胞，并比较肾脏和肺部的局部和远程伤害反应 在Aki之后。我们的中心假设是（1）PTC衍生的TNF是AKI-ALI介体，（2）本地和遥控器 免疫反应具有共同特征，但具有重要的差异。我们的初步工作表明 PTC衍生的TNF介导炎症和CCR2+依赖性的间质巨噬细胞募集到肺部， 并靶向肺间隙巨噬细胞。我们在本地和远程伤害反应中发现相似之处 例如，肺对AKI与急性心肌梗塞的反应有显着差异。理由 项目是完成（1）将PTC衍生的TNF识别为AKI-ALI介体和肺间隙 巨噬细胞作为肺中的靶细胞，（2）确定局部特征和显着差异 以及可以用于靶向疗法的远程免疫反应。我们计划测试中央 假设有两个特定的目的：目标1：确定PTC衍生的TNF和TNFR1间隙的作用 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及其异质性中的巨噬细胞，并比较局部肾脏免疫细胞对遥控器的反应 AKI-ALI中的肺免疫细胞反应（使用命运映射和SCRNASEQ）。作为结果，我们希望TNF- PTC-KO可以防止AKI-ALI，并且对局部和远程伤害反应的比较确定了重要 差异。这项贡献很重要，因为预计它将对发展产生翻译影响 具有高死亡率的继发性AKI并发症的治疗方法，例如Aki-Ali。我们的研究是创新的， 我们认为，因为它首次确定源（PTC）和目标细胞（间隙 肾脏中的Aki-Ali介体的巨噬细胞_，首次使用单细胞RNASEQ定义本地 和远程免疫反应Aki-Ali。