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: 9810994
• 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/9810994
• 关键词: Address; Alzheimer' s Disease; Arrhythmia; Base Pairing; Binding; Binding Sites; Bioinformatics; Biological; Biological Models; Biology; Blood Vessels; Brain; Cardiac; 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; body map; cardiogenesis; cardiometabolism; 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 心力衰竭是世界范围内发病率和死亡率的主要原因。心脏的发病和临床病程 失败是由环境和遗传因素复杂的相互作用决定的。人口研究已经 发现了许多与心脏病有关的遗传联系，然而，许多变体本质上是非编码的， 而我们理解这些联系的能力受到了我们对浩瀚宇宙的有限了解的阻碍 控制循环系统基因表达的基因组调控系统。最近，microRNAs(MiRs)已经 成为心脏生物学和疾病中的关键基因调节因子。这些小的非编码RNA被加载到 通过与目标转录本进行碱基配对来指导转录后基因抑制的ArgAerte(AGO)蛋白， 值得注意的是，破坏这一调控的基因变异与疾病有关。要了解miR函数 以及它们与遗传学和心脏病的联系，确定它们的靶点是至关重要的。不幸的是， 在人类心脏组织中，缺乏经验性的miR靶向数据，减缓了MIR的翻译影响 许多与疾病相关的微核率的研究。为了支持这些努力，我们的首要目标是定义MIR 靶向事件及其在人类心脏中的生物学相关性，并了解其临床意义 改变心脏miR功能的遗传变异。在这项授权中，我们将解决识别miR绑定的限制 利用高通量技术研究心脏病发病机制和遗传基础的重要部位 对人类心脏组织中miR-靶点的相互作用进行全局分析。中心假设有两个方面：1) MIR-靶相互作用在衰竭的人类心脏中显著重新连接，2)遗传变异(例如SNPs) 干扰这些相互作用将影响心脏病的临床病程。在目标1中，我们将填充重要的 通过生成转录组范围的图谱来了解心脏MIR的机制靶点 在“正常”的非衰竭和衰竭的人类心脏组织中存在MIR结合位点。生成的数据将指向 可能调节心肌病和心律失常相关miR靶相互作用的翻译相关SNPs (在目标2中进行了测试)，有可能揭示有助于疾病异质性的新的遗传修饰物。 最后，在目标3中，我们将确定这种性质的SNPs是否与临床结果有关(例如，存活和死亡 心律失常)在多个心力衰竭患者队列中，发现可能影响 病人管理。此外，我们将超越基本的基因型-表型联系，以深入了解 通过定义全球心肌基因表达特征的特定基因型变化来揭示潜在的机制。 总体而言，这项工作将1)广泛地促进我们对心脏miR功能的了解，2)促进翻译 心脏病的遗传学研究走向新的致病机制和个性化改进 医学，以及3)支持未来的努力，将miR靶向的“身体地图”扩展到 与具有复杂遗传基础的其他流行的多因素心脏代谢疾病有关。