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：
10442711
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/10442711
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.

项目概要心力衰竭 (HF) 越来越受到研究人员的关注，预计到 2020 年心力衰竭发生率将增加 25% 2030. 心力衰竭是一种极其复杂的疾病，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。心力衰竭病因复杂，风险常见高血压、糖尿病等因素本身是多因素的。因此，有一个人群在疾病发生和进展方面存在巨大的异质性，这掩盖了已证实常见心力衰竭形式具有很强的遗传成分。由于这种异质性，人类全基因组关联研究只能恢复少数重要基因座。最近，PI 研究小组描述了一组小鼠，其中鉴定了 30 多个与 HF 相关表型的位点，并且与人类中显着或暗示的 HF 相关位点表现出显着重叠 (50%)。该提案概述了这组小鼠的扩展，以探索心脏的表观基因组儿茶酚胺刺激前后。使用新颖的实验技术和计算工具，该提案旨在识别控制 DNA 甲基化的重要基因和途径。它还寻求连接 DNA 甲基化对 HF 相关表型变化的影响以及概述广泛的职业发展计划让Rau博士在王博士的指导下完成他的培训并过渡到独立通过建立心血管遗传学和多学科研究项目来确立学术地位基因组学。在该奖项的 K99 阶段，Rau 博士将分析 88 种小鼠的甲基化组使用还原代表性亚硫酸氢盐测序在儿茶酚胺刺激之前和之后。研究将重点关注使用甲基化和表型数据来识别表观基因组范围内的 CpG 表型关联关联研究基因座。将检查基因型-甲基化关联以确定 DNA 的位点突变导致整个基因组 DNA 甲基化存在巨大差异。通过将这些位点与 Rau 博士将根据之前在该小组中收集的大量数据来预测因果基因和途径与 HF 有关。根据初步结果，在奖励的 K99 部分期间，PI 还将在使用 CRISPR/Cas9 基因敲除系统对两个高可信度候选基因进行体内功能研究： Mospd3 调节心脏重量，Serpina3n 参与 1800 多个 CpG 的调节。在 R00 部分，PI 会将 K99 部分中识别的基因与其体内训练结合起来验证以确定导致心力衰竭的新基因和途径。拟议研究的总体目标是整合系统生物学、表观遗传学和分子生物学分析以加深对调节 DNA 甲基化和 HF- 的遗传途径的了解相关表型。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiomyocyte ploidy is dynamic during postnatal development and varies across genetic backgrounds.

心肌细胞倍性在出生后发育过程中是动态的，并且随着遗传背景的不同而变化。

DOI：
发表时间：
2023-04-01
期刊：
影响因子：
0
作者：
Swift, Samantha K;Purdy, Alexandra L;Kolell, Mary E;Andresen, Kaitlyn G;Lahue, Caitlin;Buddell, Tyler;Akins, Kaelin A;Rau, Christoph D;O'Meara, Caitlin C;Patterson, Michaela
通讯作者：
Patterson, Michaela