Regulation of Cardiomyocyte Maturation

心肌细胞成熟的调节

• 批准号: 10334508
• 负责人: William Tswenching Pu
• 金额: $ 58.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334508
• 关键词: Adult; Animals; Calcium; Cardiac Myocytes; Cardiac development; Cell Cycle; Cell Respiration; Cell membrane; Cells; Characteristics; Chromatin; Collection; Complex; Contracts; Data; Development; Distal; Enhancers; Epigenetic Process; GATA4 gene; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Heart; Heart Abnormalities; Heart Diseases; Heart failure; Human; Intercellular Junctions; Ion Channel; Knowledge; Life; Methods; Molecular; Mosaicism; Mus; Mutation; Myocardial; Myocardial dysfunction; Natural regeneration; Nuclear Receptors; Patients; Performance; Perinatal; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Positioning Attribute; Process; Pump; RNA Polymerase II; Reader; Regulation; Role; Sarcomeres; Shapes; Signal Pathway; Signaling Molecule; Signaling Protein; Stress; Survivors; TAF1 gene; TAF2 gene; TAF3 gene; Techniques; Testing; Time; congenital heart disorder; crystallinity; embryonic stem cell; fetal; frontier; gene function; in vivo; in vivo evaluation; innovation; loss of function; mutant; novel; novel therapeutics; postnatal; programs; promoter; stem cells; success; tool; transcription factor

Project Summary/Abstract Adult cardiomyocytes (CMs) are specialized to forcefully contract and relax billions of times during an animal's lifetime. A number of adaptations allow adult CMs to fulfill this role, including: large, elongated shape; highly organized network of cell-cell junctions; reliance on oxidative metabolism; nearly crystalline array of sarcomeres; characteristic organization of calcium release units around a network of plasma membrane invaginations known as T-tubules; cell cycle exit; and expression of adult CM-specific contractile, calcium handling, and ion channel genes. In mouse, most of these adaptations are acquired in the first three postnatal weeks. Little is known about the molecular regulation of the CM maturation program. This information gap limits development of rational approaches to stimulate maturation of stem-cell derived CMs. Furthermore, it is likely that congenital heart disease mutations or abnormal cardiac stress caused by congenital heart malformations impact CM maturation, with implications for long term myocardial performance of congenital heart disease patients. Our long term goal is to understand the regulatory program that governs CM maturation. Our preliminary data show that GATA4 and GATA6 (GATA4/6) transcription factors are essential for CM maturation. In addition, a forward genetic screen uncovered TAF3, a component of the RNA Polymerase II pre-initiation complex and a reader of H3K4me3 epigenetic marks, as a novel maturation regulators. Using a number of unique and novel tools and approaches, this proposal will investigate mechanisms that control CM maturation. Aim 1 will dissect the mechanisms by which GATA4 and GATA6 regulate enhancer activity during CM maturation. Aim 2 will further characterize TAF3 mutants and dissect the mechanisms by which it regulates maturation. Aim 3 will apply our innovative in vivo forward genetic screen to discover signaling molecules and congenital heart disease genes that are essential for CM maturation. The coordinated transformation of fetal CMs to their mature counterparts is among the least well understood aspects of cardiac development. Success with this proposal's aims will advance our knowledge in this unexplored frontier of cardiac development.

项目概要/摘要 成体心肌细胞 (CM) 专门用于在一次运动过程中强力收缩和舒张数十亿次。 动物的一生。许多适应使得成年 CM 能够履行这一角色，包括：大而细长的形状； 高度组织化的细胞与细胞连接网络；对氧化代谢的依赖；近乎晶体阵列 肌节；质膜网络周围钙释放单元的特征组织 称为 T 形管的内陷；细胞周期退出；和成人 CM 特异性收缩、钙的表达 处理和离子通道基因。在小鼠中，大多数这些适应是在出生后的前三年内获得的 几周。关于 CM 成熟程序的分子调控知之甚少。这种信息差距 限制了刺激干细胞衍生的 CM 成熟的合理方法的发展。此外，它是 可能是先天性心脏病突变或先天性心脏病引起的异常心脏应激 畸形影响 CM 成熟，对先天性心肌病的长期心肌性能产生影响 心脏病患者。 我们的长期目标是了解控制 CM 成熟的监管计划。我们的 初步数据表明GATA4和GATA6 (GATA4/6)转录因子对于CM至关重要 成熟。此外，正向遗传筛选发现了 TAF3，它是 RNA 聚合酶 II 的一个组成部分 前起始复合物和 H3K4me3 表观遗传标记的读取器，作为一种新型的成熟调节因子。使用 许多独特和新颖的工具和方法，该提案将研究控制 CM 的机制 成熟。目标 1 将剖析 GATA4 和 GATA6 调节增强子活性的机制 CM 成熟。目标 2 将进一步表征 TAF3 突变体并剖析其调节机制 成熟。 Aim 3 将应用我们创新的体内正向遗传筛选来发现信号分子和 先天性心脏病基因对于 CM 成熟至关重要。 胎儿 CM 与其成熟对应物的协调转化是最差的之一 了解心脏发育的各个方面。该提案目标的成功将提高我们的知识 这是心脏发育的一个未探索的领域。

项目成果

Molecule in mothers' milk nurses pups' heart cells to maturity.

母乳中的分子将幼崽的心脏细胞哺育至成熟。

• DOI: 10.1038/d41586-023-01635-4
• 发表时间: 2023
• 期刊: Nature
• 影响因子: 64.8
• 作者: Zhou,Pingzhu;Pu,WilliamT
• 通讯作者: Pu,WilliamT

Efficient In Vivo Homology-Directed Repair Within Cardiomyocytes.

• DOI: 10.1161/circulationaha.120.052383
• 发表时间: 2022-03-08
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Zheng, Yanjiang;VanDusen, Nathan J.;Butler, Catalina E.;Ma, Qing;King, Justin S.;Pu, William T.
• 通讯作者: Pu, William T.

The architecture and function of cardiac dyads.

• DOI: 10.1007/s12551-020-00729-x
• 发表时间: 2020-08-01
• 期刊: Biophysical reviews
• 作者: Lu, Fujian;Pu, William T
• 通讯作者: Pu, William T

A shared role of the myocardin-family transcriptional coactivators in cardiomyocyte maturation.

心肌素家族转录共激活因子在心肌细胞成熟中的共同作用。

• DOI: 10.1007/s11427-023-2385-x
• 发表时间: 2023
• 期刊: Science China. Life sciences
• 作者: Guo,Yuxuan;Cao,Yangpo;Jardin,BlakeD;Mazumdar,Neil;Guo,Congting;Yang,Luzi;Lin,Junsen;Chen,Zhan;Ma,Qing;Zhao,Mingming;Dong,Erdan;Pu,WilliamT
• 通讯作者: Pu,WilliamT