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：
JACQUELINE HO
金额：
$ 36.95万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
https://reporter.nih.gov/project-details/10338136
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Affect Angiogenic Factor Animals Blood Vessels Blood capillaries Blood flow Chronic Kidney Failure Critical Illness Data Endothelial Cells Endothelium Epithelial Family Hypoxia In Vitro Inflammatory Injury Injury to Kidney Inpatients Intervention Investigation Kidney Knowledge Laboratories MicroRNAs Modeling Molecular Morbidity - disease rate Patients Predisposition Recovery Renal function Reperfusion Injury Risk Role Sepsis Testing Thrombospondin 1 Time Transcript Transgenic Mice Tubular formation Work angiogenesis cecal ligation puncture endothelial repair gain of function high risk in vivo injury and repair injury recovery loss of function member mortality nephrogenesis new therapeutic target novel therapeutic intervention renal ischemia repaired reparative capacity response targeted treatment therapeutic target therapy development transcriptome sequencing tumorigenesis vascular 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.

抽象的据估计，约 20% 的住院患者和近 50% 的重症住院患者遭受痛苦急性肾损伤 (AKI) 与高发病率和死亡率相关。而肾可能会康复，但患者随后患慢性肾病（CKD）的风险较高；其他有时，急性损伤非常严重，以至于肾脏无法恢复。 AKI 的标志之一是损伤肾脏微血管。这种损伤改变内皮功能，导致缺氧和炎症肾实质损伤。尽管血管生成反应（血管从现有血管中萌芽）肾脏微血管系统是内皮细胞修复（以及 AKI 恢复）的关键，被认为具有有限的功能。修复能力。目前没有针对 AKI 的具体疗法，也没有可用的干预措施降低 AKI 后进展为 CKD 的风险。目前的大部分干预措施都集中在肾小管上上皮。为了开发针对该疾病的治疗方法，需要解决一些知识差距肾脏微血管，包括：（1）AKI后驱动内皮修复的分子机制是什么； (2) AKI 后是否可以调节肾微血管的修复能力？我们实验室此前已证明miR-17~92簇（包括微小RNA（miRNA）：miR-17、 miR-18a、miR-19a/b、miR-20a 和 miR-92a) 是正常肾脏发育和功能所必需的。这个集群已知可调节其他细胞环境中的血管生成，例如肿瘤发生。信息有限关于 AKI 中肾血管系统中 miRNA 的研究，而 miR-17~92 在这方面的作用尚不清楚。我们的研究小组在肾缺血再灌注损伤（IRI）后生成了初步数据，表明转基因内皮细胞中缺乏miR-17~92的小鼠更容易受到肾IRI的影响。我们的中心假设是 miR- 17~92 促进内皮细胞损伤后修复，预防AKI；从而使其成为一种令人兴奋的治疗方法目标。为了检验这一假设，提出了以下具体目标：目标 1- 定义以下要求：肾损伤和修复过程中内皮miR-17~92的变化；目标2-确定miR-17~92是否足够以防止肾损伤。