MicroRNA-21 in Renal Aging

MicroRNA-21 在肾脏衰老中的作用

基本信息

批准号：
8306690
负责人：
Markus Bitzer
金额：
$ 7.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306690
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Age Aging Animal Model Apoptosis Apoptotic Atrophic Biological Process Cell Death Cessation of life Chronic Chronic Kidney Failure Code Communities Creatinine Data Deposition Development Dialysis procedure Disease Early Diagnosis Elderly Epithelial Cells Exhibits Extracellular Matrix Failure Family Fibrosis Functional RNA Future Gene Expression Gene Expression Profile Genes Histologic Human In Vitro Individual Inflammation Inflammatory Injury Injury to Kidney Intervention Investigation Ischemia Kidney Kidney Failure Knockout Mice Knowledge Lead Left Measures Mediating Mediator of activation protein Messenger RNA MicroRNAs Molecular Molecular Profiling Mus Mutant Strains Mice NF-kappa B Nucleotides Outcome Partner in relationship Pathway Analysis Pathway interactions Patients Pattern Pharmaceutical Preparations Play Predisposition Process RNA Recovery Regulation Renal function Reperfusion Injury Reperfusion Therapy Risk Rodent Role Serum Signal Transduction Small RNA Societies Stress Structure Survivors Systems Biology Therapeutic Therapeutic Intervention Time Tissues Transforming Growth Factor beta Tubular formation age related biological systems computerized tools cost genome-wide glomerulosclerosis high risk improved in vivo insight interest interstitial mortality novel novel strategies prevent renal ischemia response response to injury senescence young adult

项目摘要

DESCRIPTION (provided by applicant): Age (>60yrs) is associated with increased mortality after acute kidney injury (AKI) with survivors being left with chronic kidney disease and on dialysis costing $10 billion per year. Components of the underlying mechanism that lead from AKI to failure to recover kidney function and CKD have been identified using animal models including ischemia-reperfusion injury. Increased apoptosis, inflammation and deposition of extracellular matrix result in renal fibrosis and renal failure. Persistent activation of pro-inflammatory and pro-fibrotic signals are important mediators of this process. It is not understood well why older individuals are at increased risk for delayed, incomplete or absent recovery after AKI. The NF-kappaB pathway has been identified as an activator of age-related transcriptional changes in human and rodents and is thought to mediate development of both GS and TIF following tissue injury. Micro-RNAs have recently been found to play an important role in coordinating the apoptotic and pro-fibrotic response to NF-kappaB activation. microRNAs (miRs), are small RNA molecules (19-22 nucleotides long) that coordinate pathways of gene expression via partial complementary to target mRNAs. They are a particularly attractive avenue for investigation because of their therapeutic potential as long-lasting drugs that can modulate molecular pathways. Our preliminary data show delayed recovery from ischemia-reperfusion injury in young adult miR-21 knockout mice. In addition, miR-21 inhibits apoptosis in cultured renal epithelial cells. Because we detected increasing miR-21 expression in the kidney during aging, we hypothesize that this increased miR-21 expression plays a protective role that prevents activation of the apoptotic and pro-fibrotic pathway activation in response to injury through inhibiting components of the NF-kappaB pathway and crosstalk with p53 and TGF-beta signaling. We propose to determine whether loss of miR-21 alters the response to ischemia-reperfusion injury associated with aging by examining renal function, histologic changes and cellular mechanisms known to mediate IR injury in miR-21 null mice. Furthermore, we will define the underlying mechanism of age-associated changes and its regulation by miR-21 in the renal response to IR injury using genome-wide expression profiling and a systems biology approach to compare patterns of transcriptional network structures. We expect that old mice lacking miR-21 will exhibit increased susceptibility to ischemia-reperfusion than young mice and their wildtype litter-mates with an intact miR-21 regulatory machinery. Demonstration of this protective relationship for miR-21 will open up the possibility that this micro-RNA could be used therapeutically.

描述（由申请人提供）：年龄（> 60岁）与急性肾脏损伤（AKI）后的死亡率增加有关，幸存者每年患有慢性肾脏疾病和透析量为100亿美元。已经使用包括缺血 - 再灌注损伤在内的动物模型鉴定了从AKI到未能恢复肾功能和CKD的基本机制的组成部分。细胞外基质的凋亡，炎症和沉积增加导致肾纤维化和肾衰竭。促炎和促纤维化信号的持续激活是此过程的重要介体。为什么年龄较大的人会增加延迟，不完整或不恢复后的风险，这尚不清楚。 NF-kappab途径已被确定为人和啮齿动物中与年龄相关的转录变化的激活因子，被认为可以介导组织损伤后GS和TIF的发展。最近发现微RNA在协调对NF-kappab激活的凋亡和纤维化反应方面起着重要作用。 microRNA（miR）是小的RNA分子（长19-22个核苷酸），它们通过部分互补与靶MRNA进行了基因表达的途径。由于可以调节分子途径的持久药物，因此它们是一个特别有吸引力的研究途径。我们的初步数据表明，年轻的成年miR-21敲除小鼠中缺血 - 再灌注损伤的恢复延迟。另外，miR-21抑制培养的肾上皮细胞中的凋亡。由于我们在衰老过程中检测到肾脏中MiR-21的表达增加，因此我们假设增加了miR-21表达起着保护性作用，可以防止通过抑制NF-kappab途径的抑制成分，与p53和tgf-beta的crosstalk抑制损伤的成分，从而阻止了凋亡和纤维化途径激活的激活。我们建议通过检查肾功能，组织学变化和已知可介导miR-21 null小鼠IR损伤的肾功能，组织学变化和细胞机制，是否会改变与衰老相关的缺血 - 再灌注损伤的反应。此外，我们将使用全基因组表达分析和一种比较转录网络结构模式的系统生物学方法来定义与年龄相关变化的基本机制及其对IR损伤的肾脏响应中对IR损伤的肾脏反应的基本机制。我们预计，缺乏miR-21的老鼠比幼鼠及其具有完整的miR-21调节机械的野生型垃圾伴侣会表现出更大的敏感性。对miR-21的保护关系的证明将打开可用于治疗的微RNA的可能性。