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

• 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
• 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

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.

项目总结/摘要 在人类心脏中表达的主要肌球蛋白重链β-MyHC由MYH 7基因编码。 MYH 7变异体在肥厚型心肌病中有很好的描述，在扩张型心肌病中不太常见。 心肌病最近的一系列出版物将MYH 7基因5'端的变异与左半胱氨酸相关。 心室致密化不全性心肌病，通常发生在功能受损的心室扩张的情况下。 重要的是，MYH 7基因内的过早截短以及错义变异与LVNC有关 无论是在人口研究中还是在个人和家庭中。我们现在产生了一个杂合子早产儿 在人诱导多能干细胞（hiPSC）中MYH 7的截短。当分化成工程化的 在人心脏组织中，我们观察到MYH 7中的杂合性过早截短产生表型 与过度增殖和功能降低相一致，这是被认为是 LVNC在体内的发展。我们假设在LVNC中鉴定的截短和错义变体是 与收缩力降低相关，而不是在肥厚性心肌病中观察到的高动力MYH 7变体。 心肌病此外，MYH 7中的许多错义变体被认为是不确定的MYH 7的变体。 这里所使用的意义和方法可能有助于判断风险的变化。通过这个 根据K99阶段的培训计划，门罗博士将评估与LVNC相关的错义MYH 7变体 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 使用心脏成像和基因型数据，在人群中研究LVNC相关MYH 7变异。 在人口数据集中。随着门罗博士过渡到他的独立阶段，他将根据所做的工作 在他的火车上暗示了河马途径在增殖和规范中的作用。在目标3中，他将详细介绍新的 使用已经建立的模型，在MYH 7相关LVNC中，对Yes相关蛋白（雅普）的疾病相关性进行了研究。 并在K99培训中进一步发展。最后，在目标4中，门罗博士使用无偏见的方法， 表征健康和LVNC工程化心脏组织中的人心肌细胞异质性， 更好地描绘分化的范围，并确定其他下游途径，将燃料未来 调查事务所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，将侧重于扩大他的管理和他自己的指导技能。他 发展计划包括正式和非正式的课程和讲习班，旨在促进多样性，公平， 提高心血管健康的研究生产力。