Acute kidney injury and microbiome

急性肾损伤和微生物组

基本信息

  • 批准号:
    10628833
  • 负责人:
  • 金额:
    $ 2.58万
  • 依托单位:
  • 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

项目摘要

Contact PD/PI: RABB, HAMID 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. Project Summary/Abstract Page 7
联系PD/PI:Rabb,Hamid 项目摘要/摘要 急性肾损伤(AKI)相关的发病率和死亡率是一个主要的临床问题,涉及 重叠的病理生理机制。我们团队和其他人最近的观察表明 肠道微生物区系调节AKI的结果,然而涉及肠道的潜在机制 微生物区系-肾脏的串扰,特别是在恢复阶段,仍然知之甚少。我们的工作 这项拨款申请的假设是肠道微生物区系诱导肾脏T细胞群体的特定变化 以调节AKI的转归和康复。此外,我们假设短链脂肪酸(SCFA) 由某些肠道微生物群产生的物质通过特定的嗅觉受体与肾脏组织进行通讯,如G 蛋白偶联受体41(Gpr41)、嗅觉受体78(Olfr78)和Olfr558存在于肾脏。测试我们的 假设,我们将(AIM 1)免疫表型肾免疫细胞从野生型(WT)、抗生素治疗(AB) 和无菌(GF)小鼠在基线、AKI早期和缺血和顺铂恢复期间 诱导AKI。我们将利用T细胞缺陷小鼠、T细胞抗体耗竭和 针对特定T细胞(例如,CD4、Tregs、CD3+CD4-CD8-双阴性)的过继转移研究,以确定 选择T细胞在AKI微生物群效应中的作用。以免疫为重点的元基因组学和代谢组学 将在AKI和RECOVER中测量炎症途径,以确定微生物群落和 代谢物。我们还将对特定细菌、抗炎粪便进行定植研究(来自 在AB处理组、GF和WT小鼠中使用益生菌。此外,内毒素释放的影响,从 在使用Toll样受体4(TLR4)的研究中,肾脏免疫细胞群上的肠漏将被调查。 有缺陷的小鼠。研究SCFA信号受体在肠道微生物区系肾串扰(AIM 2)中的作用 我们将在Gpr41-/-、Olfr78-/-和Olfr558-/-小鼠中诱导AKI,以描述SCFA信号在AKI中的作用 恢复。我们将确定免疫细胞或常驻肾内皮细胞/上皮源的SCFA相互作用 Gpr41、Olfr78和Olfr558通过评估肾脏和免疫细胞特异性SCFA受体缺陷小鼠和 进行骨髓移植。此外,产生超临界脂肪酸的细菌和外源超临界脂肪酸将 应用于Gpr41-/-、Olfr78-/-和Olfr558-/-小鼠,观察其对AKI结果的影响。为了让我们的 与人类AKI更相关的实验室研究,我们将(目标3)对大便前后样本进行元基因组学 和血液代谢组学在心脏手术患者中发现肠道微生物区系之间的差异 那些发展AKI的和那些受到保护的。我们将从以下方面调查人类微生物区系的影响 在AB治疗、GF小鼠和SCFA受体缺陷小鼠中发生AKI的患者。成功完成 这些研究将有助于了解肠道微生物区系-肾脏串扰的免疫学效应,并可能是新的 治疗方案涉及单链脂肪酸和目标肠道微生物区系,用于急性肾功能衰竭和康复。 项目摘要/摘要第7页

项目成果

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HAMID RABB其他文献

HAMID RABB的其他文献

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{{ truncateString('HAMID RABB', 18)}}的其他基金

Acute kidney injury and microbiome
急性肾损伤和微生物组
  • 批准号:
    10214606
  • 财政年份:
    2020
  • 资助金额:
    $ 2.58万
  • 项目类别:
Acute kidney injury and microbiome
急性肾损伤和微生物组
  • 批准号:
    10630061
  • 财政年份:
    2020
  • 资助金额:
    $ 2.58万
  • 项目类别:
Acute kidney injury and microbiome
急性肾损伤和微生物组
  • 批准号:
    10395550
  • 财政年份:
    2020
  • 资助金额:
    $ 2.58万
  • 项目类别:
Targeting T lymphocyte Keap1 for acute kidney injury
靶向 T 淋巴细胞 Keap1 治疗急性肾损伤
  • 批准号:
    9333374
  • 财政年份:
    2016
  • 资助金额:
    $ 2.58万
  • 项目类别:
Antigen Discovery in Acute Kidney Injury
急性肾损伤中抗原的发现
  • 批准号:
    7989727
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:
Targeting oxidative stress modifiers in acute kidney injury
针对急性肾损伤的氧化应激调节剂
  • 批准号:
    8074925
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:
Antigen Discovery in Acute Kidney Injury
急性肾损伤中抗原的发现
  • 批准号:
    8107544
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:
Targeting oxidative stress modifiers in acute kidney injury
针对急性肾损伤的氧化应激调节剂
  • 批准号:
    8279457
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:
Targeting oxidative stress modifiers in acute kidney injury
针对急性肾损伤的氧化应激调节剂
  • 批准号:
    8470636
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:
Targeting oxidative stress modifiers in acute kidney injury
针对急性肾损伤的氧化应激调节剂
  • 批准号:
    7898113
  • 财政年份:
    2010
  • 资助金额:
    $ 2.58万
  • 项目类别:

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ATTAC 时间:针对 gp100 细胞的 T 细胞过继转移来治疗 LAM
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