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.

项目摘要/摘要在人心脏中表达的主要肌球蛋白重链是由MYH7基因编码的。 MYH7变体在肥厚性心肌病中得到很好的描述，而在扩张中却较少见心肌病。最近的一系列出版物链接在MYH7基因5末端的链接变体，如左图所示心室非功能性心肌病通常是在功能受损的脑室的情况下。重要的是，MYH7基因内的过早截断和错义变化与LVNC有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人类诱导多能干细胞（HIPSC）中MyH7的截断。当分为工程人类心脏组织，我们观察到MYH7中的杂合过早截断会产生表型与多余的增殖和功能降低一致，这是关键特征，认为这是 LVNC在体内的开发。我们假设LVNC中确定的截断和错义变体是与降低的收缩力相关，而不是肥厚型中观察到的过度动态MYH7变体心肌病。此外，MYH7中的许多错义变体被认为是不确定的变体重要性和方法（例如这里使用的方法）可能有助于调整风险的变体。通过这个在K99阶段的培训计划，Monroe博士将评估与LVNC相关的MYH7变种并评估其在工程心组织中的表现。在第二个目标中，他将扩大寻找 LVNC相关的MYH7与人口量表的变化使用链接的心脏成像和基因型数据在人口数据集中。随着门罗博士过渡到他的独立阶段，他将从上班的工作中建立在他的火车早些时候，在扩散和规格中暗示了河马途径。在AIM 3中，他将详细介绍使用已在MYH7相关的LVNC中，使用已经在MYH7相关的LVNC中的疾病相关性在他的K99培训下，手并进一步发展。最后，在AIM 4中，梦露博士使用公正的方法来表征健康和LVNC设计的心脏组织中人类心肌细胞异质性更好地描述差异的范围，并确定将推动未来推动未来的其他下游途径调查。为了促进他的职业发展，门罗博士将借鉴他的心理力量委员会和主要导师将着重于扩大他的管理和自己的指导技能。他的发展计划包括旨在促进多样性，公平和的正式课程和非正式课程和讲习班研究生产力致力于改善心血管健康。