Acute kidney injury and microbiome

急性肾损伤和微生物组

基本信息

批准号：
10395550
负责人：
HAMID RABB
金额：
$ 59.19万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395550
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adoptive Transfer Affect Anti-Inflammatory Agents Antibiotics Antibodies Antiinflammatory Effect Applications Grants Bacteria Binding Blood Bone Marrow Transplantation CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cardiac Surgery procedures Cells Cisplatin Clinic Clinical Creatinine Data Endothelium Endotoxins Ensure Epithelial Evaluation FFAR3 gene Feces Germ-Free Human Immune Immunologics Immunology Immunophenotyping Inflammation Inflammatory Injury Injury to Kidney Ischemia Kidney Kidney Diseases Kidney Transplantation Knockout Mice Link LoxP-flanked allele Measures Mediating Metabolic Metagenomics Modeling Molecular Morbidity - disease rate Mus Outcome Pathway interactions Patient-Focused Outcomes Patients Phase Phenotype Population Probiotics Process Property Publishing Receptor Signaling Recovery Regulatory T-Lymphocyte Reperfusion Therapy Research Role Serum Signal Transduction Smell Perception Source T-Lymphocyte TLR4 gene Testing Therapeutic Studies Tissues Translating Tubular formation Volatile Fatty Acids Wild Type Mouse Work endotoxin receptor experimental study gut bacteria gut microbiome gut microbiota hemodynamics human microbiota immune activation improved injury and repair injury recovery kidney cell metabolomics microbial microbial community microbiome microbiota mortality murine colitis novel novel marker novel therapeutics olfactory receptor pregnant programmed cell death ligand 1 programmed cell death protein 1 receptor renal ischemia repaired response stool sample tool

项目摘要

Project Summary /Abstract Acute kidney Injury (AKI) associated morbidity and mortality is a major clinical problem that involves multiple overlapping pathophysiological mechanisms. Recent observations from our team and others demonstrated that intestinal microbiota modulates AKI outcome, however the underlying mechanism involved in intestinal microbiota-kidney crosstalk, especially during the recovery phase, remain poorly understood. Our working hypothesis for this grant application is that gut microbiota induces specific changes in the kidney T cell population to mediate AKI outcome and recovery. Furthermore, we hypothesize that short chain fatty acids (SCFAs) produced by certain gut microbiota communicate with kidney tissue via specific smell receptors, such as G protein coupled receptor 41 (Gpr41), olfactory receptor 78 (Olfr78) and Olfr558 present in the kidney. To test our hypotheses, we will (AIM 1) immunophenotype kidney immune cells from wild type (WT), antibiotic treated (AB) and germ free (GF) mice at baseline, during the early phase of AKI, and during recovery of ischemic and cisplatin induced AKI. We will conduct mechanistic studies using T cell deficient mice, T cell antibody depletion and adoptive transfer studies targeting select T cells (e.g. CD4, Tregs, CD3+CD4-CD8- double neg) to determine roles of select T cells on microbiome effects on AKI. Metagenomic and metabolomics with focus on immune inflammatory pathways will be measured in AKI and recovery for identification of microbial communities and metabolites. We will also perform colonization studies with specific bacteria, anti-inflammatory stool (from pregnant mice) and probiotics in AB treated, GF and WT mice. Furthermore, effect of endotoxin released from leaking gut on renal immune cells population will be investigated in studies using toll like receptor 4 (TLR4) deficient mice. To study the role of SCFA signaling receptors in intestinal microbiota–kidney crosstalk (AIM 2) we will induce AKI in Gpr41-/-, Olfr78-/- and Olfr558-/- mice to delineate role of SCFA signaling during AKI recovery. We will identify immune cell or resident kidney endothelium/epithelial source of SCFA interaction with Gpr41, Olfr78 and Olfr558 by evaluating kidney and immune cell specific SCFA receptor deficient mice and performing bone marrow transplants. Additionally, SCFA producing bacteria and exogenous SCFAs will be administered to Gpr41-/-, Olfr78-/- and Olfr558-/- mice and its effect examined on AKI outcomes. To make our lab studies more relevant to human AKI, we will (AIM 3) perform metagenomics of pre and post stool samples and blood metabolomics from patients undergoing cardiac surgery to find gut microbiota differences between those that develop AKI and those that are protected. We will investigate the effect of human microbiota from patients that develop AKI in AB treated, GF mice and SCFA receptor deficient mice. Successful completion of these studies will help understand immunological effects of gut microbiota-kidney crosstalk and potentially novel treatment options involving SCFAs and targeting intestinal microbiota, for AKI and recovery.

项目摘要 /摘要急性肾脏损伤（AKI）相关的发病率和死亡率是一个主要的临床问题，涉及多个重叠的病理生理机制。我们团队和其他人的最新观察表明肠道菌群调节AKI结果，但是肠道涉及的潜在机制尤其是在恢复阶段，微生物群 - 基德尼的串扰，对恢复阶段的理解仍然很差。我们的工作该赠款应用的假设是肠道菌群诱导肾脏T细胞种群的特定变化调解AKI的结果和恢复。此外，我们假设短链脂肪酸（SCFA）由某些肠道菌群通过特定的气味接收器与肾脏组织交流，例如蛋白偶联受体41（GPR41），嗅觉受体78（OLFR78）和OLFR558肾脏中存在。测试我们的假设，我们将（AIM 1）免疫表型肾脏免疫细胞（WT），抗生素处理（AB）（AB）在基线，AKI的早期以及缺血性和顺铂恢复期间，无菌（GF）小鼠（GF）小鼠诱发的Aki。我们将使用缺乏T细胞的小鼠，T细胞抗体部署和针对特定T细胞的收养转移研究（例如CD4，Treg，CD3+CD4-CD8-双负）确定选择T细胞对微生物组对AKI的作用的作用。宏基因组学和代谢组学专注于免疫炎症途径将在AKI中测量，并恢复微生物群落和代谢物。我们还将使用特定细菌，抗炎粪便进行定殖研究（来自 AB治疗，GF和WT小鼠中的孕妇小鼠）和益生菌。此外，内毒素的作用肠道渗漏对肾脏免疫核管种群将在使用TOLL像受体4（TLR4）的研究中研究不足的小鼠。研究SCFA信号受体在肠道微生物群 - Kidney Crosstalk中的作用（AIM 2）我们将在gpr41 - / - ，olfr78 - / - 和olfr558 - / - 小鼠中诱导AKI，以描绘AKI期间SCFA信号的作用恢复。我们将确定与SCFA相互作用的肾脏内皮/上皮来源的免疫细胞或居民 GPR41，OLFR78和OLFR558通过评估肾脏和免疫球特异性SCFA受体缺乏小鼠，并且进行骨髓移植。此外，SCFA产生细菌和外源SCFA将是施用到GPR41 - / - ，OLFR78 - / - 和OLFR558 - / - 小鼠及其对AKI结果的影响。让我们的实验室研究与人类AKI更相关，我们将（AIM 3）执行粪便前和后粪便样品的宏基因组学和接受心脏手术的患者的血液代谢组学发现肠道菌群差异那些发展AKI和受到保护的人。我们将研究人类微生物群的影响在AB治疗，GF小鼠和SCFA受体缺乏小鼠中发展的AKI的患者。成功完成这些研究将有助于理解肠道微生物群 - 基德尼串扰和潜在新颖的免疫学影响涉及SCFA和靶向肠道菌群的治疗方案，用于AKI和恢复。