Molecular regulation of ventricular chamber maturation

心室成熟的分子调节

基本信息

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
项目类别：
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

项目摘要

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.

抽象的先天性心脏病是人类出生缺陷中最常见的类型，其中许多疾病具有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生长胚胎的需求，发育中的心脏经历复杂的形态发生变化以优化其心室肌结构可实现更有效的收缩。该提案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心脏小梁形成是由心肌细胞从致密层定向迁移启动的， ErbB2 细胞自主调节这一过程。我们还发现生物力学产生的力心脏小梁的形成需要有功能的胚胎心脏的支持。然而，有几个悬而未决的问题仍有待解决，包括与 1）机械刺激感知机制相关的问题并转化为空间和时间信号来调节心脏小梁，2) 的确切功能心脏中的心脏小梁。人们已经认识到，心脏与心脏之间存在着密切的关系。功能和心脏形态。在这个研究项目中，我们假设机械生化相互作用是对于心脏小梁的形成至关重要，并在缺乏的情况下诱导病理性肥厚重塑小梁形成。为了支持这一假设，我们发现需要初级纤毛介导的流量传感通过激活心室心内膜中的 Notch 信号来形成小梁。虽然生物力学力需要启动小梁，我们的初步研究还揭示了心脏小梁的重要作用处理心脏收缩产生的机械力。为了检验我们的假设，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。该提案的成功完成不仅将定义心室成熟的分子和细胞机制，同时也提供了对心室成熟的进一步机制的了解。心脏功能和心脏形态之间的相互关系。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

Molecular and cellular basis of embryonic cardiac chamber maturation.

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

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

DOI：
10.1007/978-1-0716-0668-1_12
发表时间：
2021
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Xu J;Wang L;Liu J;Qian L
通讯作者：
Qian L

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