Non-Coding RNA and CKD Progression

非编码 RNA 和 CKD 进展

基本信息

批准号：
10242892
负责人：
Dominic S Raj
金额：
$ 67.85万
依托单位：
GEORGE WASHINGTON UNIVERSITY
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：
2020-08-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242892
关键词：
Biological Biological Markers Biological Process Blood Cell Communication Cells Chronic Kidney Failure Chronic Kidney Insufficiency Cicatrix Clinical Clinical Data Cohort Studies Data Detection Diagnosis Disease Disease Progression Distant Early Diagnosis End stage renal failure Etiology Evaluation Event Exhibits Fibrosis Genes Glomerular Filtration Rate Human In Vitro Inflammation Injury to Kidney Intervention Kidney Kidney Diseases Laboratories Lead Link Liquid substance Measures MicroRNAs Mus Participant Pathogenicity Pathologic Processes Pathway interactions Phase Phenotype Physiological Physiological Processes Plasma Play Prevalence Process Proteinuria Renal function Repression Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Transduction Staging Testing Therapeutic Time Tissues Transforming Growth Factor beta Untranslated RNA Urine Validation base biobank cohort early detection biomarkers experimental study extracellular improved in vivo innovation intercellular communication interest kidney fibrosis loss of function mouse model next generation next generation sequencing primary outcome prognostic response risk stratification therapeutic target translational approach urinary

项目摘要

Project Summary Kidney fibrosis is the final common pathway downstream of most renal injuries that contributes to progressive chronic kidney disease (CKD). Non-coding RNAs regulate kidney fibrosis through direct repression and/or expression of matrix genes and through TGF-β signaling. Our central working hypothesis is that specific circulating and urinary microRNA and long non-coding RNA (EncRNA) are indicators of underlying kidney fibrosis and hence are early biomarkers for CKD progression. We will use the Chronic Renal Insufficiency Cohort Study (CRIC) biosamples and associated data. The study will be conducted in three phases; discovery, replication and an experimental validation phases. Next-generation sequencing will be used to profile the ncRNAs in blood and urine samples from participants exhibiting slow (n=191) and fast (n=192) progression of CKD. Top CKD progression-related ncRNA discoveries will be replicated in 3,088 CRIC study participants using quantitative RT- PCR. The primary renal phenotypes of interest are the slope of change in estimated glomerular filtration rate (eGFR), and either time to end-stage kidney disease (ESRD), or a composite of time to ESRD or a 50% reduction in eGFR. We will employ innovative in vitro experiments and in vivo gain and loss of function experiments in mouse models to identify targets and validate the functional significance of the EncRNA discoveries from human studies. Finally, we will verify the expression level of the top EncRNA discoveries in the microdissected CKD kidney tissues. Identification of specific ncRNA pathways for the progression of CKD will enhance diagnosis, enable risk stratification and lead to hypothesis driven targeted interventions.

项目概要肾纤维化是大多数肾损伤的最终共同下游途径，导致进行性肾损伤非编码 RNA 通过直接抑制和/或调节肾纤维化。我们的中心工作假设是特定的基质基因的表达和 TGF-β 信号传导。循环和尿液中的 microRNA 和长链非编码 RNA (EncRNA) 是潜在肾纤维化的指标因此是 CKD 进展的早期生物标志物，我们将使用慢性肾功能不全队列研究。（CRIC）生物样本和相关数据将分三个阶段进行；实验验证阶段将用于分析血液中的 ncRNA。以及表现出缓慢 (n=191) 和快速 (n=192) CKD 进展的参与者的尿液样本。与进展相关的 ncRNA 发现将在 3,088 名 CRIC 研究参与者中使用定量 RT- 进行复制 PCR。感兴趣的主要肾脏表型是估计肾小球滤过率的变化斜率。 (eGFR)，以及至终末期肾病 (ESRD) 的时间，或至 ESRD 的时间的综合或减少 50% 在 eGFR 中，我们将采用创新的体外实验和体内功能获得和丧失实验。小鼠模型来识别靶点并验证人类 EncRNA 发现的功能意义最后，我们将验证显微解剖 CKD 中最重要的 EncRNA 发现的表达水平。识别 CKD 进展的特定 ncRNA 途径将增强诊断，实现风险分层并导致假设驱动的有针对性的干预措施。