Discovery of Novel Epigenetic Regulators of Heart Failure in a Panel of Mice

在一组小鼠中发现心力衰竭的新型表观遗传调节因子

基本信息

批准号：
10213814
负责人：
Christoph Daniel Rau
金额：
$ 24.9万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213814
关键词：
Adrenergic beta-Agonists Affect Award Biological Biological Process CRISPR/Cas technology Candidate Disease Gene Cardiac Cardiac Myocytes Cardiovascular system Catecholamines Chromatin Structure Chronic Clinical Complex DNA DNA Methylation DNA Methylation Regulation DNA Modification Process DNA Sequence Alteration DNA Structure Data Data Set Development Plans Diabetes Mellitus Diagnosis Disease Disease Progression Elderly Environment Environmental Risk Factor Epigenetic Process Etiology Foundations Functional disorder Generations Genes Genetic Genetic Polymorphism Genome Genomics Genotype Goals Heart Heart Hypertrophy Heart failure Heritability Heterogeneity Human Human Genome Hybrids Hypertension Hypertrophy In Vitro Inbred Strains Mice Interdisciplinary Study Isoproterenol Knockout Mice Lead Left Link Masks Measures Mediating Mentorship Methods Methylation Modification Molecular Analysis Mouse Strains Mus Myocardial dysfunction Onset of illness Pathologic Pathology Pathway interactions Patients Phase Phenotype Play Population Population Study Positioning Attribute Public Health Quantitative Trait Loci Regulation Reporting Research Research Personnel Risk Factors Role Site Source Suggestion System Systems Biology Techniques Tissues Training Treatment Cost Validation Variant Ventricular Weight base bisulfite sequencing career development causal variant cohort computerized tools disorder prevention epigenome epigenome-wide association studies genetic analysis genetic approach genome wide association study genome-wide genome-wide analysis genomic variation in silico in vivo insight interest knockout gene methylation pattern methylome novel patient population phenotypic data population based programs response stressor tool trait transcriptome

项目摘要

PROJECT SUMMARY Heart failure (HF) is a growing concern among researchers, with rates expected to increase by 25% by 2030. HF is an incredibly complex disease with many pathological features including cardiomyocyte hypertrophy, contractile dysfunction and fibrotic remodeling. HF has complex etiologies, with common risk factors such as hypertension and diabetes being in and of themselves multi-factorial. Consequently, there is a tremendous amount of heterogeneity in human populations in both disease onset and progression which mask the demonstrated strong genetic component of common forms of HF. As a result of this heterogeneity, human genome-wide association studies have only been able to recover a handful of significant loci. Recently, the PI's group described a population of mice in which over 30 loci for HF-related phenotypes were identified and which demonstrated significant overlap (50%) with significant or suggestive HF-associated loci in humans. This proposal outlines an extension of this panel of mice to explore the epigenome of the heart both before and after catecholamine stimulation. Using novel experimental techniques and computational tools, the proposal seeks to identify important genes and pathways which control DNA methylation. It also seeks to connect DNA methylation to changes in HF-related phenotypes as well as outlining an extensive career development plan for Dr. Rau to complete his training under the mentorship of Dr. Wang and transition to an independent academic position by establishing a multi-disciplinary research program in cardiovascular genetics and genomics. During the K99 phase of this award, Dr. Rau will analyze the methylomes of 88 strains of mice both before and after catecholamine stimulation using reduced representation bisulfite sequencing. Research will focus on the use of methylation and phenotypic data to identify CpG-phenotype associations at epigenome-wide association study loci. Genotype-methylation associations will be examined to identify loci within which DNA mutations drive large differences in DNA methylation across the genome. By combining these loci with the significant amount of data previously gathered in this panel, Dr. Rau will predict causal genes and pathways implicated in HF. Based on preliminary results, during the K99 portion of the award the PI will also perform in vivo functional studies using the CRISPR/Cas9 gene knockout system of two high-confidence candidate genes: Mospd3, which regulates heart weight and Serpina3n, which is implicated in the regulation of over 1800 CpGs. During the R00 portion, the PI will combine the genes identified during the K99 portion with his training in in vivo validation to identify novel genes and pathways which contribute to heart failure. The overall goal of the proposed studies is to integrate systems biology, epigenetics and molecular analyses to lead to deeper understandings of the genetic pathways which regulate DNA methylation and HF- related phenotypes.

项目摘要心力衰竭（HF）在研究人员中越来越关注，预计利率将增加25％ 2030。HF是一种非常复杂的疾病，具有许多病理特征，包括心肌细胞肥大，收缩功能障碍和纤维化重塑。 HF具有复杂的病因，具有共同风险高血压和糖尿病等因素本身是多因素的。因此，有一个疾病发作和进展中，人口中的异质性大量的异质性掩盖了 HF的共同形式证明了强的遗传成分。由于这种异质性，人类全基因组关联研究仅能够恢复少数重要的基因座。最近，PI 小组描述了一群小鼠，其中发现了30多个基因座，用于HF相关的表型，并在人类中表现出显着的重叠（50％），具有显着性或暗示性HF相关的基因座。该提议概述了该小鼠小鼠的扩展，以探索心脏的表观质量儿茶酚胺刺激前后。使用新颖的实验技术和计算工具，提案旨在确定控制DNA甲基化的重要基因和途径。它也试图连接 DNA甲基化对HF相关表型的变化以及概述了广泛的职业发展计划让劳博士在王博士的指导下完成培训，并过渡到独立通过在心血管遗传学和基因组学。在该奖项的K99阶段，Rau博士将分析88种小鼠菌株的甲基团在儿茶酚胺刺激前后，使用降低表示的硫酸盐测序。研究将专注于使用甲基化和表型数据来识别范围远期组的CpG-表型关联协会研究基因座。将检查基因型 - 甲基化关联以识别DNA的基因座突变驱动了整个基因组的DNA甲基化的巨大差异。通过将这些基因座与先前在此面板中收集的大量数据，Rau博士将预测因果基因和途径与HF有关。根据初步结果，在奖励的K99部分中，PI也将在使用两个高信心候选基因的CRISPR/CAS9基因敲除系统的体内功能研究：调节心脏重量和serpina3n的MOSPD3与1800多个CPG相关。在R00部分期间，PI将在K99部分中鉴定的基因与他在体内的培训相结合验证以识别有助于心力衰竭的新型基因和途径。该研究的总体目标是整合系统生物学，表观遗传学和分子分析会导致对调节DNA甲基化和HF-的遗传途径的更深入理解相关表型。