Non-Coding RNA and CKD Progression

非编码 RNA 和 CKD 进展

• 批准号: 10670205
• 负责人: Dominic S Raj
• 金额: $ 36.89万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10670205
• 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; Link; Liquid substance; Measures; MicroRNAs; Mus; Participant; Pathogenicity; Pathologic Processes; Pathway interactions; Phase; Phenotype; Physiological; Physiological Processes; Plasma; Play; Prevalence; Process; Proteinuria; Quantitative Reverse Transcriptase PCR; RNA replication; Renal function; Repression; Role; Sampling; Signal Transduction; Staging; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Untranslated RNA; Urine; Validation; biobank; cohort; disease prognosis; early detection biomarkers; experimental study; extracellular; gain of function; improved; in vivo; innovation; intercellular communication; interest; kidney fibrosis; loss of function; mouse model; next generation; next generation sequencing; primary outcome; risk stratification; therapeutic target; translational approach; treatment response; urinary

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.

项目摘要 肾纤维化是大多数肾脏损伤下游的最终常见途径，导致进步 慢性肾脏病（CKD）。非编码RNA通过直接表达和/或调节肾纤维化 基质基因的表达和通过TGF-β信号传导。我们的中心工作假设是特定的 循环和泌尿肌瘤和长的非编码RNA（EncRNA）是潜在肾脏纤维化的指标 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。该研究将分为三个阶段；发现，复制 和实验验证阶段。下一代测序将用于介绍血液中的NCRNA 和参与者的尿液样本表现出慢速（n = 191）和CKD的快速（n = 192）。顶级CKD 与进展相关的NCRNA发现将在3,088个CRIC研究参与者中使用定量RT-复制 pcr。感兴趣的主要肾脏表型是估计肾小球过滤率的变化斜率 （EGFR），以及终阶段肾脏疾病（ESRD）的时间，或者是ESRD的综合时间或减少50％ 在EGFR中。我们将采用创新的体外实验和体内增益和功能实验的丧失 小鼠模型识别目标并验证人类发现的功能意义 研究。最后，我们将验证微解析CKD中顶部encRNA发现的表达水平 肾脏组织。鉴定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目标干预措施。

项目成果

Dietary Protein and Fiber Affect Gut Microbiome and Treg/Th17 Commitment in Chronic Kidney Disease Mice.

• DOI: 10.1159/000526957
• 发表时间: 2022
• 期刊: AMERICAN JOURNAL OF NEPHROLOGY
• 影响因子: 4.2
• 作者: Serrano, Myrna;Srivastava, Anvesha;Buck, Gregory;Zhu, Bin;Edupuganti, Laahirie;Adegbulugbe, Esther;Shankaranarayanan, Divya;Kopp, Jeffrey B.;Raj, Dominic S.
• 通讯作者: Raj, Dominic S.

Race, Interleukin-6, TMPRSS6 Genotype, and Cardiovascular Disease in Patients With Chronic Kidney Disease.

• DOI: 10.1161/jaha.122.025627
• 发表时间: 2022-09-20
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Barrows, Ian R.;Devalaraja, Matt;Kakkar, Rahul;Chen, Jing;Gupta, Jayanta;Rosas, Sylvia E.;Saraf, Santosh;He, Jiang;Go, Alan;Raj, Dominic S.;Amdur, Richard L.
• 通讯作者: Amdur, Richard L.

Alterations of gut microbial pathways and virulence factors in hemodialysis patients.

• DOI: 10.3389/fcimb.2022.904284
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

• DOI: 10.1016/j.kint.2022.06.022
• 发表时间: 2022-11
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Dember, Laura M.;Hung, Adriana;Mehrotra, Rajnish;Hsu, Jesse Y.;Raj, Dominic S.;Charytan, David M.;Mc Causland, Finnian R.;Regunathan-Shenk, Renu;Landis, J. Richard;Kimmel, Paul L.;Kliger, Alan S.;Himmelfarb, Jonathan;Ikizler, T. Alp
• 通讯作者: Ikizler, T. Alp