Molecular regulation of ventricular chamber maturation

心室成熟的分子调节

• 批准号: 10369641
• 负责人: Jiandong Liu
• 金额: $ 40.17万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369641
• 关键词: 3-Dimensional; Address; Adult; Biochemical; Biological Models; Biomechanics; Calcium Channel; Cardiac; Cardiac Jelly; Cardiac Myocytes; Cell Transplantation; Cells; Cilia; Complex; Computer Models; Congenital Abnormality; Congenital cardiomyopathy; Data; Defect; Deterioration; Development; Disease; Dominant-Negative Mutation; ERBB2 gene; Embryo; Embryonic Development; Embryonic Heart; Endocardium; Event; Exhibits; Failure; Future; Genes; Genetic; Genetic Epistasis; Heart; Heart Diseases; Human; Lead; Mechanics; Mediating; Modeling; Molecular; Molecular Genetics; Morphogenesis; Muscle; Myocardial; Myocardial dysfunction; Organ; Pathologic; Permeability; Phenotype; Physiological; Play; Process; Pump; Radial; Regulation; Reporting; Research; Resolution; Role; Series; Signal Pathway; Signal Transduction; Stress; Structural defect; Structure; Testing; Time; Translating; Tube; Ventricular; Ventricular Function; Work; Zebrafish; congenital heart disorder; disease phenotype; genetic approach; heart function; improved; insight; interdisciplinary approach; malformation; mechanical force; mechanical stimulus; migration; mutant; notch protein; novel; programs; public health relevance; response; screening; small molecule; spatiotemporal; tool

Abstract Congenital heart diseases are the most common type of human birth defects, and many of these diseases feature structural abnormalities that emerge during development. In order to meet an increasing physiological demand of the growing embryo, the developing heart undergoes complex morphogenetic changes to optimize its ventricular myoarchitecture for more efficient contraction. This proposal is focused on ventricular maturation that is characterized by the formation of muscular protrusions called cardiac trabeculae. Our prior studies revealed that cardiac trabeculation is initiated by directional cardiomyocyte migration from the compact layer, and that ErbB2 cell-autonomously regulates this process. We also found that biomechanical forces generated by the functioning embryonic heart is required for cardiac trabeculation. However, several outstanding questions remain to be addressed, including those related to 1) the mechanism by which mechanical stimulus is sensed and translated into spatial and temporal signals to regulate cardiac trabeculation and 2) the exact function of cardiac trabeculae in the heart. It has been recognized that there exists an intimate relationship between cardiac function and cardiac form. In this research program, we hypothesize that mechanical-biochemical interaction is essential for cardiac trabecular formation and induces pathological hypertrophic remodeling in the absence of trabecular formation. In support of this hypothesis, we found that primary cilia-mediated flow sensing is required for trabeculation through activation of Notch signaling in the ventricular endocardium. While biomechanical forces are required to initiate trabeculation, our preliminary study also revealed an essential role of cardiac trabeculae in handling the mechanical forces generated by cardiac contraction. To test our hypothesis, we propose to further delineate the mechanical-biochemical cellular signaling responsible for 1) trabecular formation, and 2) cardiac dysfunction due to trabecular malformation. The successful completion of this proposal will not only define the molecular and cellular mechanisms of ventricular maturation but also provide further mechanistic insight into the inter-relationship between cardiac function and cardiac form.

摘要 先天性心脏病是人类出生缺陷中最常见的类型，其中许多疾病 在发育过程中出现的结构异常。为了满足日益增长的生理需求， 为了满足不断生长的胚胎的需求，发育中的心脏经历了复杂的形态发生变化， 它的心室肌结构更有效的收缩。这项建议的重点是心室成熟 其特征是形成称为心脏小梁的肌肉突起。我们之前的研究 揭示了心脏小梁形成是由致密层的定向心肌细胞迁移启动的， ErbB 2细胞自主调节这一过程。我们还发现，生物力学的力量产生， 是心脏小梁形成所必需的。然而，几个悬而未决的问题 仍然有待解决，包括那些与1）机械刺激被感知的机制有关的问题 并转化为空间和时间信号以调节心脏小梁形成，以及2） 心脏中的心脏小梁。人们已经认识到，心脏病与心血管疾病之间存在着密切的关系。 功能和心脏形态。在这项研究计划中，我们假设机械-生物化学相互作用是 对心脏小梁形成至关重要，并在缺乏的情况下诱导病理性肥大性重塑。 小梁形成为了支持这一假设，我们发现初级纤毛介导的流量传感是必需的 通过激活心室内膜中的Notch信号传导来形成小梁。虽然生物力学力量 我们的初步研究也揭示了心脏小梁的重要作用， 来处理心脏收缩产生的机械力。为了验证我们的假设，我们建议进一步 描述负责1）小梁形成和2）心脏的机械-生化细胞信号传导 由于小梁畸形导致的功能障碍。这项提案的成功完成不仅将确定 心室成熟的分子和细胞机制，但也提供了进一步的机制洞察， 心功能与心脏形态的相互关系。

项目成果

Delineating chromatin accessibility re-patterning at single cell level during early stage of direct cardiac reprogramming.

• DOI: 10.1016/j.yjmcc.2021.09.002
• 发表时间: 2022-01
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Wang H;Yang Y;Qian Y;Liu J;Qian L
• 通讯作者: Qian L

Direct cardiac reprogramming comes of age: Recent advance and remaining challenges.

• DOI: 10.1016/j.semcdb.2021.07.010
• 发表时间: 2022-03
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Xie Y;Liu J;Qian L
• 通讯作者: Qian L

In Vitro Conversion of Murine Fibroblasts into Cardiomyocyte-Like Cells.

鼠的成纤维细胞体外转化为心肌细胞样细胞。

• DOI: 10.1007/978-1-0716-0668-1_12
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Xu J;Wang L;Liu J;Qian L
• 通讯作者: Qian L

Molecular and cellular basis of embryonic cardiac chamber maturation.

胚胎心脏腔室成熟的分子和细胞基础。

• DOI: 10.1016/j.semcdb.2021.04.022
• 发表时间: 2021-10
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Dong Y;Qian L;Liu J
• 通讯作者: Liu J

Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification.

Notch 信号在心脏形态发生和小梁规范过程中以时空依赖性方式调节 Hey2 表达。

• DOI: 10.1038/s41598-018-20917-w
• 发表时间: 2018-02-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Miao L;Li J;Li J;Tian X;Lu Y;Hu S;Shieh D;Kanai R;Zhou BY;Zhou B;Liu J;Firulli AB;Martin JF;Singer H;Zhou B;Xin H;Wu M
• 通讯作者: Wu M