Mechanisms linking the frail sarcomere to noncompaction cardiomyopathy

脆弱肌节与非致密化心肌病的相关机制

基本信息

批准号：
10643016
负责人：
Tanner O Monroe
金额：
$ 10.89万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643016
关键词：
Address Alleles Bioinformatics Cardiac Cardiac Myocytes Cardiomyopathies Cell Cycle Cell Line Cells Childhood Code Complex Cytoskeleton DNA sequencing Data Data Discovery Data Set Defect Development Development Plans Developmental Biology Dilated Cardiomyopathy Disease Educational workshop Electronics Equity Family Functional disorder Future General Population Genes Genetic Genetic Variation Genomics Genotype Hand Head Health Heart Heart Diseases Heterogeneity Heterozygote Human Human Engineering Hypertrophic Cardiomyopathy Impairment Individual Investigation Left ventricular non-compaction Link Loss of Heterozygosity Mediating Medical Mentors Methods Modeling Molecular Motor Mutation Myosin ATPase Myosin Heavy Chains N-terminal Non-compaction cardiomyopathy Outcome Pathogenicity Pathway interactions Performance Phase Phenocopy Phenotype Population Population Study Prevalence Productivity Proliferating Proteins Publications Research Resources Sarcomeres Secondary to Series Signal Transduction Specific qualifier value Study models Testing Tissue Engineering Tissues Training Training Programs United States National Institutes of Health Variant Work adjudication biobank cardiac tissue engineering cardiogenesis cardiovascular health career development cohort developmental genetics deviant disorder risk genetic approach genetic architecture genetic variant genome editing heart imaging human tissue improved in vivo indexing induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes inherited cardiomyopathy loss of function pleiotropism premature risk variant single-cell RNA sequencing skills trait transcriptomics variant of unknown significance

项目摘要

Project Summary/Abstract The predominant myosin heavy chain expressed in human heart, beta-MyHC, is encoded by the MYH7 gene. MYH7 variants are well described in hypertrophic cardiomyopathy and less frequently seen in dilated cardiomyopathy. A recent series of publications link variants in the 5’ end of the MYH7 gene as implicated in left ventricular noncompaction cardiomyopathy, often in the setting of a dilated ventricle with impaired function. Importantly, premature truncations as well as missense variation within the MYH7 gene has been linked to LVNC in both population studies and in individuals and families. We now generated a heterozygous premature truncation in MYH7 in human induced pluripotent stem cells (hiPSCs). When differentiated into engineered human heart tissues, we observe the heterozygous premature truncation in MYH7 produces a phenotype consistent with excess proliferation and reduced function, which are key features thought to underlie the development of LVNC in vivo. We hypothesize that truncations and missense variants identified in LVNC are associated with reduced contractility, rather than hyperdynamic MYH7 variants seen in hypertrophic cardiomyopathy. Additionally, many missense variants in MYH7 are considered variants of uncertain significance and methods such as those being used here may help adjudicate variants of risk. Through this training program under the K99 phase, Dr. Monroe will evaluate missense MYH7 variants associated with LVNC and evaluate their performance in engineered heart tissues. In his second aim, he will expand the search for LVNC-associated MYH7 variation to the population scale using linked cardiac imaging and genotype data in the in population datasets. As Dr. Monroe transitions to his independent phase, he will build from work performed earlier in his train implicating the Hippo pathway in proliferation and specification. In Aim 3, he will detail new disease relevance for the Yes-associated protein (YAP) in MYH7-associated LVNC using the models already in hand and further developed under his K99 training. Finally, in Aim 4, Dr. Monroe uses unbiased approaches to characterize human cardiomyocyte heterogeneity in healthy and LVNC engineered heart tissues in order to better delineate the range of differentiation and identify additional downstream pathways that will fuel future investigations. To promote his career development, Dr. Monroe will draw on the strengths of his mentoring committee and primary mentor which will focus on expanding his management and his own mentoring skills. His development plan includes formal and informal courses and workshops aimed at promoting diversity, equity, and research productivity directed towards improving cardiovascular health.

项目概要/摘要在人类心脏中表达的主要肌球蛋白重链，β-MyHC，由 MYH7 基因编码。 MYH7 变异在肥厚型心肌病中得到了充分描述，但在扩张型心肌病中较少见。最近的一系列出版物将 MYH7 基因 5' 端的变异联系起来，如左图所示。心室致密化不全心肌病，通常发生在心室扩张且功能受损的情况下。重要的是，MYH7 基因内的过早截短以及错义变异与 LVNC 相关在人口研究以及个人和家庭中，我们现在产生了杂合的早产儿。当分化为工程细胞时，人类诱导多能干细胞 (hiPSC) 中 MYH7 发生截短。在人类心脏组织中，我们观察到 MYH7 中的杂合性过早截短产生了表型与过度增殖和功能减少相一致，这是被认为是潜在的关键特征我们勇敢地面对 LVNC 中发现的截短和错义变异。与收缩力降低相关，而不是肥大中看到的高动力 MYH7 变异此外，MYH7 中的许多错义变异被认为是不确定的变异。重要性和方法（例如此处使用的方法）可能有助于通过此判断风险的变体。 K99阶段的培训计划中，Monroe博士将评估与LVNC相关的错义MYH7变异并评估它们在工程心脏组织中的表现。在他的第二个目标中，他将扩大对心脏的研究。使用关联的心脏成像和基因型数据研究 LVNC 相关的 MYH7 变异对人群规模的影响当门罗博士过渡到他的独立阶段时，他将从所做的工作中进行构建。在他的火车早期，他将在目标 3 中详细介绍 Hippo 途径的增殖和规范。使用已有的模型确定 MYH7 相关 LVNC 中 Yes 相关蛋白 (YAP) 的疾病相关性最后，在目标 4 中，Monroe 博士使用公正的方法来实现。表征健康和 LVNC 工程心脏组织中的人类心肌细胞异质性，以便更好地描绘差异化范围并确定将推动未来发展的其他下游途径为了促进他的职业发展，门罗博士将利用他的指导优势。委员会和主要导师将专注于扩大他的管理和他自己的指导技能。发展计划包括旨在促进多样性、公平性和研究生产力旨在改善心血管健康。