The genomic interface of microRNA regulation and heart failure

microRNA调控与心力衰竭的基因组界面

• 批准号: 10199883
• 负责人: RYAN L BOUDREAU
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199883
• 关键词: Address; Alzheimer' s Disease; Arrhythmia; Base Pairing; Binding; Binding Sites; Biological; Biological Models; Biology; Blood Vessels; Brain; Cardiac; Cardiometabolic Disease; Cardiomyopathies; Cardiovascular system; Cause of Death; Cessation of life; Clinical; Clinical Data; Complex; DNA; Data; Disease; Event; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Research; Genetic Transcription; Genetic Translation; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Grant; Healthcare Systems; Heart; Heart Diseases; Heart failure; High-Throughput Nucleotide Sequencing; Human; Inherited; Investigation; Investments; Knowledge; Left; Link; Maps; Mediating; Messenger RNA; Methods; MicroRNAs; Morbidity - disease rate; Myocardial; Nature; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Patient-Focused Outcomes; Patients; Phenotype; Population Study; Predisposing Factor; Prevalence; Proteins; RNA; Regulation; Regulator Genes; Reporting; Research; Resources; Risk Factors; SNP genotyping; Sampling; Site; Structure; System; Techniques; Testing; Tissue Sample; Tissues; Transcript; Untranslated RNA; Variant; Ventricular; Woman; Work; bioinformatics pipeline; body map; cardiogenesis; clinically significant; cohort; cost; crosslink; crosslinking and immunoprecipitation sequencing; disease heterogeneity; genetic risk factor; genetic variant; human data; human disease; human subject; human tissue; in vitro Assay; in vivo; insight; mRNA Expression; men; mortality; neuropsychiatry; novel; novel therapeutics; personalized medicine; prevent; public health relevance; response; sudden cardiac death; transcriptome; transcriptomics; translational impact

PROJECT SUMMARY / ABSTRACT Heart failure is a primary cause of morbidity and mortality worldwide. The onset and clinical course of heart failure is dictated by a complex interplay of environmental and hereditary factors. Population studies have identified a number of genetic links to heart disease, however, many of the variants are non-coding in nature, and our ability to make sense of these associations has been hampered by our limited knowledge of the vast genomic regulatory system that controls circulatory system gene expression. Recently, microRNAs (miRs) have emerged as key gene regulators in cardiac biology and disease. These small non-coding RNAs are loaded into Argonaute (Ago) proteins to direct post-transcriptional gene suppression by base-pairing with target transcripts, and notably, genetic variants disrupting this regulation have been linked to disease. To understand miR functions and their interface with genetics and heart disease, identifying their targets sites is paramount. Unfortunately, there is a paucity of empirical miR targeting data in human cardiac tissues, slowing the translational impact of the many investigations of disease-relevant miRs. To bolster these efforts, our overarching goal is to define miR targeting events and their biological-relevance in human hearts and to understand the clinical significance of genetic variants that alter cardiac miR functions. In this grant, we will address limitations in identifying miR binding sites important to the pathogenesis and genetic basis of heart disease by employing high-throughput techniques to globally profile miR-target interactions in human cardiac tissues. The central hypothesis is two-fold: 1) that miR-target interactions are significantly rewired in failing human hearts, and 2) that genetic variations (e.g. SNPs) perturbing these interactions will impact the clinical course of heart disease. In Aim 1, we will fill significant knowledge gaps regarding the mechanistic targets of cardiac miRs by generating transcriptome-wide maps of miR binding sites in “normal” non-failing and failing human heart tissues. The resulting data will point to translationally-relevant SNPs that may modulate cardiomyopathy- and arrhythmia-related miR-target interactions (tested in Aim 2), having the potential to reveal new genetic modifiers that contribute to disease heterogeneity. Finally, in Aim 3, we will determine if SNPs of this nature are linked to clinical outcomes (e.g. survival and fatal arrhythmias) in multiple heart failure patient cohorts, discovering novel inherited risk factors that could impact patient management. In addition, we will push beyond basic genotype-phenotype links to gain insight into the underlying mechanisms by defining genotype-specific changes in global myocardial gene expression signatures. Overall, this work will 1) broadly advance our knowledge of cardiac miR functions, 2) facilitate the translation of genetic studies of heart disease towards novel pathogenic mechanisms and improvements in personalized medicine, and 3) support future efforts to extend the “body map” of miR targeting to vascular tissues that are related to other prevalent multifactorial cardio-metabolic diseases with complex genetic underpinnings.

项目摘要 /摘要 心力衰竭是全球发病率和死亡率的主要原因。心脏的发作和临床过程 失败取决于环境和遗传因素的复杂相互作用。人口研究有 确定了许多与心脏病的遗传联系，但是，许多变体本质上是非编码的， 我们对这些关联的理解能力受到了我们对新的知识的有限了解 控制电路系统基因表达的基因组调节系统。最近，microRNA（mirs）具有 成为心脏生物学和疾病中的关键基因调节剂。这些小型非编码RNA被加载到 Argonaute（AGO）蛋白通过与目标转录本碱基对指导转录后基因抑制， 值得注意的是，破坏该调节的遗传变异与疾病有关。了解mir功能 以及它们与遗传学和心脏病的界面，确定其目标部位至关重要。很遗憾， 在人类心脏组织中靶向数据的经验miR很少，从而减慢了翻译的影响 与疾病相关的miR的许多投资。为了加强这些努力，我们的总体目标是定义mir 针对人类心脏中的事件及其生物学发展，并了解 改变心脏miR功能的遗传变异。在这笔赠款中，我们将解决识别mir约束力的局限性 通过采用高通量技术，对心脏病的发病机理和遗传基础很重要的站点 在人类心脏组织中全球介绍mir-target相互作用。中心假设是两个方面：1） mir靶的相互作用显着重新连接到失败的人心中，2）遗传变异（例如SNP） 扰动这些相互作用将影响心脏病的临床过程。在AIM 1中，我们将填补大量 通过生成有关心脏miR的机械目标的知识差距，通过产生全转录组图 MiR结合位点在“正常”的非失败和失败的人类心脏组织中。结果数据将指向 可以调节心肌病和心律不齐相关的mir-target相互作用的转换性SNP （在AIM 2中进行了测试），有可能揭示有助于疾病异质性的新遗传修饰剂。 最后，在AIM 3中，我们将确定这种性质的SNP是否与临床结果有关（例如生存和致命 心律失常）在多发性心力衰竭患者同伙中，发现可能影响的新遗传风险因素 患者管理。此外，我们将超越基本的基因型 - 表型链接，以深入了解 通过定义全球心肌基因表达特征的基因型特异性变化来实现基本机制。 总体而言，这项工作将1）广泛提高我们对心脏miR功能的了解，2）促进翻译 心脏病的遗传研究针对新型致病机制和个性化改善 医学和3）支持将来将miR靶向的“身体图”扩展到血管组织的“身体图”的努力 与具有复杂遗传基础的其他普遍多因素心脏代谢疾病有关。