The role of microRNAs in progressive renal decline in Type 1 diabetes

microRNA 在 1 型糖尿病肾进行性衰退中的作用

• 批准号: 10164613
• 负责人: Marcus Guy Pezzolesi
• 金额: $ 35.2万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164613
• 关键词: Biological; Collection; Complement; Coupled; Data; Development; Diabetic Nephropathy; Disease; End stage renal failure; Foundations; Future; Gene Expression; Goals; Gold; Health; Insulin-Dependent Diabetes Mellitus; Investigation; Kidney; Knowledge; Laboratories; Lead; Longitudinal Studies; Mediating; Methodology; MicroRNAs; Natural History; Participant; Pathogenesis; Patients; Physiological Processes; Pilot Projects; Plasma; Play; RNA; Regulator Genes; Renal function; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Role; Seminal; Specimen; Technology; Transforming Growth Factors; Work; base; biobank; candidate validation; cost; diabetic patient; differential expression; fibrogenesis; functional decline; improved; innovation; interdisciplinary approach; miRNA expression profiling; multidisciplinary; new therapeutic target; next generation sequencing; novel; novel marker; novel therapeutic intervention; prevent; type I diabetic

PROJECT SUMMARY Progressive renal decline is the central manifestation of diabetic nephropathy (DN) that leads to end-stage renal disease (ESRD). In participants of the Joslin Kidney Study (JKS), a longitudinal investigation of the natural history of DN in Type 1 diabetes (T1D), we recently demonstrated that microRNAs (miRNAs) involved in transforming growth factor (TGF)-β1 mediated renal fibrogenesis are deregulated early in patients who are at risk for progression to ESRD. Importantly, this deregulation occurs prior to the initiation of renal function decline, suggesting that these miRNAs have potential utility as novel biomarkers of the risk of progression to ESRD in DN. We hypothesize that additional miRNAs exist that play important roles in renal function decline in patients who are at risk of progression to ESRD but have not yet been studied. The identification of these miRNAs will lead to the discovery of novel factors involved in the pathogenesis of renal function decline. The goals of the proposed research project is to further leverage biobanked specimens from the JKS, along with innovative next-generation sequencing technology, to i) determine the expression profile of the full complement of miRNAs that are differentially expressed early in T1D patients who are at risk for progression to ESRD and prior to the initiation of renal function decline and ii) to begin to investigate the mechanisms by which these miRNAs contribute to disease pathogenesis. These goals will be accomplished through three Specific Aims. 1) To establish a comprehensive set of candidate miRNAs for early renal function decline. We will i) apply next-generation sequencing technology (miRNA-Seq) to assess miRNA levels in baseline plasma specimens from 80 non-progressors and 80 rapid progressors from the JKS and ii) define a set of candidate miRNAs for early renal function decline in T1D using robust statistical methodologies. 2) To validate the candidate miRNAs and examine their expression in additional T1D patients with early renal function decline. We will i) perform cross-platform validation (qPCR) of the candidate miRNAs identified in Aim 1 in all 80 non-progressors and 80 rapid progressors and ii) validate these miRNAs in 159 additional non-progressors and rapid progressors from the JKS. 3) To identify the miRNA:target interactions that are altered in early renal function decline. We will i) identify the biologically significant targets of the top-ranked differentially expressed candidate miRNAs identified in Aim 2 and ii) experimentally validate and functionally assess these miRNA:target interactions. Our approach is highly innovative and involves a multidisciplinary team of investigators with expertise in all aspects of the proposed research. Our implementation of this study will define currently unknown factors in DN and may lead to the identification of novel therapeutic targets to prevent progression of renal decline in T1D.

项目概要 进行性肾功能减退是糖尿病肾病 (DN) 的主要表现，可导致终末期 肾脏疾病（ESRD）。在 Joslin 肾脏研究 (JKS) 的参与者中，对 1 型糖尿病 (T1D) 中 DN 的自然史，我们最近证明 microRNA (miRNA) 涉及 转化生长因子 (TGF)-β1 介导的肾纤维化在以下患者的早期失调 有进展为 ESRD 的风险。重要的是，这种失调发生在肾功能开始之前 下降，表明这些 miRNA 具有作为进展为风险的新型生物标志物的潜在用途。 DN 中的 ESRD。我们假设存在其他 miRNA 在肾功能衰退中发挥重要作用 有进展为 ESRD 风险但尚未进行研究的患者。这些的鉴定 miRNA 将导致发现参与肾功能衰退发病机制的新因素。 拟议研究项目的目标是进一步利用 JKS 生物库样本， 与创新的下一代测序技术一起，i) 确定完整的表达谱 在有进展风险的 T1D 患者早期差异表达的 miRNA 补体 ESRD 和肾功能开始下降之前 ii) 开始研究其机制 这些 miRNA 有助于疾病的发病机制。 这些目标将通过三个具体目标来实现。 1）建立一套完整的 早期肾功能衰退的候选 miRNA。我们将 i) 应用下一代测序技术 (miRNA-Seq) 评估来自 80 个非进展者和 80 个快速者的基线血浆样本中的 miRNA 水平 来自 JKS 的进展者和 ii) 使用以下方法定义了一组用于 T1D 早期肾功能衰退的候选 miRNA 稳健的统计方法。 2) 验证候选 miRNA 并检查它们在 另外T1D患者早期肾功能下降。我们将 i) 执行跨平台验证 (qPCR) 目标 1 中在所有 80 个非进展者和 80 个快速进展者中鉴定的候选 miRNA 以及 ii) 验证 这些 miRNA 存在于来自 JKS 的 159 个其他非进展细胞和快速进展细胞中。 3) 识别 miRNA：早期肾功能衰退中改变的靶标相互作用。我们将i）从生物学上识别 目标 2 和 ii) 中确定的排名靠前的差异表达候选 miRNA 的重要靶标 通过实验验证和功能评估这些 miRNA：靶点相互作用。我们的方法是高度 具有创新性，并涉及一个由在拟议的各个方面具有专业知识的多学科研究人员组成的团队 研究。我们的这项研究的实施将定义目前未知的 DN 因素，并可能导致 确定新的治疗靶点以预防 T1D 肾功能衰退的进展。