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The genomic interface of microRNA regulation and heart failure

microRNA调控与心力衰竭的基因组界面

基本信息

批准号：
10439508
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-02 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439508
关键词：
Address Alzheimer&apos 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

项目摘要

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.

项目概要/摘要心力衰竭是全世界发病和死亡的主要原因。心脏病的发病和临床过程失败是由环境和遗传因素复杂的相互作用决定的。人口研究有确定了许多与心脏病的遗传联系，然而，许多变异本质上是非编码的，我们对这些关联的理解能力因我们对大量事物的了解有限而受到限制。控制循环系统基因表达的基因组调控系统。最近，微小RNA (miR) 成为心脏生物学和疾病中的关键基因调节因子。这些小非编码 RNA 被加载到 Argonaute (Ago) 蛋白通过与目标转录物碱基配对来指导转录后基因抑制，值得注意的是，破坏这种调节的基因变异与疾病有关。了解 miR 功能以及它们与遗传学和心脏病的相互作用，确定它们的靶位点至关重要。很遗憾，人类心脏组织中的 miR 靶向数据缺乏，减缓了 miR 的转化影响与疾病相关的 miR 的许多研究。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。在这笔资助中，我们将解决识别 miR 结合的局限性采用高通量技术确定对心脏病发病机制和遗传基础重要的位点全面分析人类心脏组织中的 miR 靶点相互作用。中心假设有两个：1） miR-靶标相互作用在衰竭的人类心脏中显着重新连接，2) 遗传变异（例如 SNP）干扰这些相互作用将影响心脏病的临床病程。在目标 1 中，我们将填补重要的通过生成全转录组图谱来弥补有关心脏 miR 机制靶标的知识差距 “正常”非衰竭和衰竭人类心脏组织中的 miR 结合位点。结果数据将指向可能调节心肌病和心律失常相关 miR 靶点相互作用的翻译相关 SNP （在目标 2 中进行测试），有可能揭示导致疾病异质性的新遗传修饰因子。最后，在目标 3 中，我们将确定这种性质的 SNP 是否与临床结果（例如生存和致命）相关。心律失常）在多个心力衰竭患者队列中，发现了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-表型联系，深入了解通过定义全局心肌基因表达特征的基因型特异性变化来了解潜在机制。总的来说，这项工作将 1) 广泛增进我们对心脏 miR 功能的了解，2) 促进心脏病的遗传学研究朝着新的致病机制和个性化的改进医学，3) 支持未来将 miR 靶向的“身体图谱”扩展到血管组织的努力与其他具有复杂遗传基础的流行多因素心脏代谢疾病有关。