Endothelial miR-17~92 protects against acute kidney injury
内皮miR-17~92预防急性肾损伤
基本信息
- 批准号:10338136
- 负责人:
- 金额:$ 36.95万
- 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:2020-03-02 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Renal Failure with Renal Papillary NecrosisAddressAffectAngiogenic FactorAnimalsBlood VesselsBlood capillariesBlood flowChronic Kidney FailureCritical IllnessDataEndothelial CellsEndotheliumEpithelialFamilyHypoxiaIn VitroInflammatoryInjuryInjury to KidneyInpatientsInterventionInvestigationKidneyKnowledgeLaboratoriesMicroRNAsModelingMolecularMorbidity - disease ratePatientsPredispositionRecoveryRenal functionReperfusion InjuryRiskRoleSepsisTestingThrombospondin 1TimeTranscriptTransgenic MiceTubular formationWorkangiogenesiscecal ligation punctureendothelial repairgain of functionhigh riskin vivoinjury and repairinjury recoveryloss of functionmembermortalitynephrogenesisnew therapeutic targetnovel therapeutic interventionrenal ischemiarepairedreparative capacityresponsetargeted treatmenttherapeutic targettherapy developmenttranscriptome sequencingtumorigenesisvascular injury
项目摘要
ABSTRACT
Approximately 20% of all hospitalized patients and nearly 50% of critically ill inpatients are estimated to suffer
from acute kidney injury (AKI), which is associated with high rates of morbidity and mortality. While the kidney
may recover, the patients are at a higher risk for subsequently developing chronic kidney disease (CKD); other
times, the acute injury is so severe that there is no kidney recovery. One of the hallmarks of AKI is damage to
the renal microvasculature. This damage alters endothelial function, contributing to hypoxic and inflammatory
injury to the renal parenchyma. Although an angiogenic response (vascular sprouting from existing vessels) is
key to endothelial cell repair (and therefore AKI recovery), the renal microvasculature is thought to have a limited
reparative capacity. There are currently no specific therapies for AKI, nor are there available interventions to
decrease the risk of progression to CKD after AKI. Much of the current interventions are focused on the tubular
epithelium. There are several knowledge gaps that need to be addressed to develop therapies targeted at the
renal microvasculature, including: (1) what are the molecular mechanisms that drive endothelial repair after AKI;
and (2) is it possible to modulate the capacity of the renal microvasculature for repair after AKI?
Our laboratory has previously shown that the miR-17~92 cluster (including the microRNAs (miRNAs): miR-17,
miR-18a, miR-19a/b, miR-20a and miR-92a) is required for normal kidney development and function. This cluster
is known to regulate angiogenesis in other cellular contexts such as tumorigenesis. There is limited information
regarding miRNAs in the renal vasculature in AKI, and the role of miR-17~92 in this context is unknown. Our
team has generated preliminary data following renal ischemia-reperfusion injury (IRI) showing that transgenic
mice lacking miR-17~92 in endothelial cells are more susceptible to renal IRI. Our central hypothesis is that miR-
17~92 promotes endothelial cell repair after injury and protects against AKI; thus making it an exciting therapeutic
target. To test this hypothesis, the following specific aims are proposed: Aim 1- To define the requirement for
endothelial miR-17~92 during renal injury and repair; and Aim 2- To determine whether miR-17~92 is sufficient
to protect against renal injury.
摘要
据估计,约20%的住院患者和近50%的重症住院患者患有
急性肾损伤(阿基)与高发病率和死亡率相关。而肾脏
可能恢复,患者随后发生慢性肾病(CKD)的风险较高;其他
有时,急性损伤如此严重,以至于肾脏无法恢复。阿基的标志之一是对
肾脏微血管系统这种损伤改变了内皮功能,导致缺氧和炎症
肾实质损伤。虽然血管生成反应(血管从现有血管发芽)是一个重要的因素,
作为内皮细胞修复(以及因此阿基恢复)的关键,肾微血管被认为具有有限的
修复能力。目前没有针对阿基的特异性疗法,也没有可用的干预措施,
降低阿基后进展为CKD的风险。目前的大部分干预措施都集中在管状
上皮有几个知识差距,需要加以解决,以开发针对的治疗,
肾微血管系统,包括:(1)阿基后驱动内皮修复的分子机制是什么;
以及(2)是否有可能调节阿基后肾脏微血管的修复能力?
我们的实验室先前已经表明,miR-17~92簇(包括microRNA(miRNAs):miR-17,
miR-18 a、miR-19 a/B、miR-20 a和miR-92 a)是正常肾脏发育和功能所必需的。此群集
已知在其它细胞环境如肿瘤发生中调节血管生成。信息有限
关于阿基中肾血管中的miRNA,miR-17~92在此背景下的作用尚不清楚。我们
研究小组在肾缺血再灌注损伤(IRI)后获得的初步数据显示,
内皮细胞中缺乏miR-17~92的小鼠更易发生肾IRI。我们的核心假设是miR-
17~92促进损伤后的内皮细胞修复并保护免受阿基;因此使其成为令人兴奋的治疗药物
目标为了检验这一假设,提出了以下具体目标:
目的2-确定miR-17 ~ 92是否足以在肾损伤和修复中发挥作用,
以防止肾损伤。
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)
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JACQUELINE HO其他文献
JACQUELINE HO的其他文献
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{{ truncateString('JACQUELINE HO', 18)}}的其他基金
Regulation of tubulointerstitial crosstalk by microRNAs in renal fibrosis
肾纤维化中 microRNA 对肾小管间质串扰的调节
- 批准号:
10749334 - 财政年份:2023
- 资助金额:
$ 36.95万 - 项目类别:
The University of Pittsburgh Summer Research Internship Program kidney workshop (SRIP-Kid)
匹兹堡大学夏季研究实习计划肾脏研讨会(SRIP-Kid)
- 批准号:
10371022 - 财政年份:2021
- 资助金额:
$ 36.95万 - 项目类别:
The University of Pittsburgh Summer Research Internship Program kidney workshop (SRIP-Kid)
匹兹堡大学夏季研究实习计划肾脏研讨会(SRIP-Kid)
- 批准号:
10623196 - 财政年份:2021
- 资助金额:
$ 36.95万 - 项目类别:
Endothelial miR-17~92 protects against acute kidney injury
内皮miR-17~92预防急性肾损伤
- 批准号:
10550222 - 财政年份:2020
- 资助金额:
$ 36.95万 - 项目类别:
Endothelial miR-17~92 protects against acute kidney injury
内皮miR-17~92预防急性肾损伤
- 批准号:
10117251 - 财政年份:2020
- 资助金额:
$ 36.95万 - 项目类别:
The Role of miR-17~92 in Nephron Progenitors
miR-17~92在肾单位祖细胞中的作用
- 批准号:
9331615 - 财政年份:2014
- 资助金额:
$ 36.95万 - 项目类别:
The Role of miR-17~92 in Nephron Progenitors
miR-17~92在肾单位祖细胞中的作用
- 批准号:
8798885 - 财政年份:2014
- 资助金额:
$ 36.95万 - 项目类别: