Harnessing hypoxia responses to treat postischemic kidney injury and inflammation

利用缺氧反应治疗缺血后肾损伤和炎症

基本信息

项目摘要

Modified Project Summary/Abstract Section Ischemia is a major cause of human acute kidney injury (AKI), a common condition in hospitalized patients with high morbidity and mortality. In ischemic AKI, hypoxic adaptation is mediated by Hypoxia-Inducible-Factors (HIF), transcriptional factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). HIF activation by pharmacologic PHD inhibition prior to renal IRI attenuates postischemic kidney injury and inflammation. The shift of cell metabolism from oxidative phosphorylation to anaerobic glycolysis has emerged as a critical factor by which PHD/HIF signaling promotes resilience to ischemia. Despite this fundamental concept, the mechanisms by which HIF affects different metabolic pathways beyond glycolysis remain unclear. Our long-term goal is to understand how hypoxic metabolic adaptation affects postischemic renal injury and repair. We recently discovered a non-canonical role for HIF signaling on tryptophan metabolism, a pathway that generates several bioactive metabolites with profound protective effects on tissues. Among them, kynurenine and kynurenic acid have emerged as metabolites that exert cytoprotective and anti-inflammatory actions but their role in AKI remains unclear. The objective of this proposal is to understand how alterations in tryptophan metabolism induced by HIF-2 affect postischemic renal injury and repair. The central hypothesis is that HIF-2 activation protects against postischemic renal injury and promotes repair through alterations in tryptophan derived metabolites kynurenine and kynurenic acid. Our rationale is that identification of the mechanism by which HIF-2 induced alterations in tryptophan metabolism provide renoprotection will create urgently needed new targeted therapeutic opportunities in the field of AKI. Our specific aim will test the following hypothesis: Activation of HIF-2 protects against AKI and promotes repair by increasing kynurenine levels systemically and in the kidney tissue in either Slc7a5- or IDO1-dependent manner. Completion of this aim will define a new paradigm in postischemic kidney injury and repair by HIF-2 activation through tryptophan metabolism and will stimulate new areas for experimental therapeutics in AKI. The proposed research is innovative because we investigate the role of hypoxic signaling in tryptophan metabolism in the context of ischemic AKI, an unexplored metabolic axis with exciting translational applications
修改项目摘要/摘要部分 缺血是人类急性肾损伤(阿基)的主要原因,AKI是住院患者的常见病症,具有高发病率和死亡率。在缺血性阿基中,缺氧适应由缺氧诱导因子(HIF)介导,HIF是其活性受脯氨酰羟化酶结构域蛋白1至3(PHD 1至PHD 3)负调控的转录因子。在肾IRI之前通过药理学PHD抑制激活HIF可减轻缺血后肾损伤和炎症。细胞代谢从氧化磷酸化到无氧糖酵解的转变已经成为PHD/HIF信号促进缺血恢复的关键因素。尽管有这个基本概念,HIF影响糖酵解以外的不同代谢途径的机制仍不清楚。我们的长期目标是了解缺氧代谢适应如何影响缺血后肾损伤和修复。我们最近发现了HIF信号对色氨酸代谢的非经典作用,这是一种产生对组织具有深远保护作用的几种生物活性代谢物的途径。其中,犬尿氨酸和犬尿烯酸已成为发挥细胞保护和抗炎作用的代谢物,但它们在阿基中的作用仍不清楚。本研究的目的是了解HIF-2诱导色氨酸代谢的改变如何影响缺血后肾损伤和修复。中心假设是HIF-2活化通过色氨酸衍生的代谢物犬尿氨酸和犬尿烯酸的改变保护免于缺血后肾损伤并促进修复。我们的基本原理是,鉴定HIF-2诱导色氨酸代谢改变提供肾保护的机制将在阿基领域创造迫切需要的新的靶向治疗机会。我们的具体目标将测试以下假设:HIF-2的激活通过以Slc 7a 5或IDO 1依赖性方式全身性和在肾组织中增加犬尿氨酸水平来保护免受阿基并促进修复。这一目标的完成将定义缺血后肾损伤和通过色氨酸代谢激活HIF-2进行修复的新范例,并将刺激阿基实验治疗的新领域。这项研究是创新的,因为我们研究了缺氧信号在缺血性阿基背景下色氨酸代谢中的作用,这是一种具有令人兴奋的翻译应用的未探索的代谢轴

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Pinelopi P. Kapitsinou其他文献

Pinelopi P. Kapitsinou的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Pinelopi P. Kapitsinou', 18)}}的其他基金

Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation
缺血性肾损伤和炎症中的内皮 PHD2/HIF 轴
  • 批准号:
    10600614
  • 财政年份:
    2017
  • 资助金额:
    $ 24万
  • 项目类别:
Endothelial PHD2/HIF Axis in Ischemic Kidney Injury and Inflammation
缺血性肾损伤和炎症中的内皮 PHD2/HIF 轴
  • 批准号:
    10301012
  • 财政年份:
    2017
  • 资助金额:
    $ 24万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 24万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了