Mechanisms of cardiomyocyte-extracellular matrix interactions in cardiogenesis

心脏发生中心肌细胞-细胞外基质相互作用的机制

• 批准号: 10291550
• 负责人: JENNIFER Schumacher
• 金额: $ 41.15万
• 依托单位: MIAMI UNIVERSITY OXFORD
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291550
• 关键词: Adult; Affect; Anterior; Arrhythmia; Atrial Heart Septal Defects; Automobile Driving; Behavior; Bilateral; Biological Assay; Birth; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Shape; Cell physiology; Cells; Child; Congenital Abnormality; Congenital Heart Defects; Defect; Development; Embryo; Endocardium; Endoderm; Environment; Epithelial; Etiology; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Genes; Goals; Growth; Heart; Heart Atrium; Heart Injuries; Heart failure; Heat-Shock Response; Histological Techniques; Human; ITGA5 gene; Infant Mortality; Integrin alpha4; Integrins; Lateral; Lead; Life; Live Birth; Medial; Mediating; Mesoderm; Microscopy; Morphogenesis; Mutation; Myocardial Infarction; Operative Surgical Procedures; Population; Prevention strategy; Proteins; Research; Role; Siblings; Signal Transduction; Stroke; System; Testing; Time; Tissue Engineering; Tissues; Transgenic Organisms; Tube; Ventricular Septal Defects; Vertebrates; Work; Zebrafish; base; cardiogenesis; cardiovascular disorder risk; cell motility; confocal imaging; heart cell; heart dimension/size; heart function; insight; loss of function mutation; migration; mutant; novel; progenitor; promoter; receptor; repaired; time use; treatment strategy

SUMMARY Proper heart development is essential for efficient heart function throughout life. Congenital heart defects (CHDs) are the most common congenital malformations, occurring in up to 1% of live births and 10% of still births. CHDs can also lead to increased risk of cardiovascular diseases in adults. During vertebrate heart development, cardiomyocyte progenitors are surrounded by a rich extracellular matrix (ECM). Mutations in several ECM proteins in humans can lead to CHDs. However, the mechanisms underlying CHDs associated with mutations that affect the ECM remain poorly understood. Signals from the ECM are detected by Integrin receptors on target cells. Our preliminary analysis of zebrafish carrying loss-of-function mutations in both the Integrin alpha5 and Integrin alpha4 genes indicate that these Integrins are reiteratively required to promote proper cardiac morphogenesis and ventricle size. The overall goal of this proposal is to elucidate mechanisms by which cardiomyocytes interpret and integrate signals from the ECM to execute proper cardiomyocyte migration and heart growth. The Specific Aims of this proposal are: Aim 1 - Determine mechanisms by which Integrin signaling mediates proper cardiomyocyte migration. This aim will use histological techniques and confocal time lapse microscopy of live embryos to test the hypothesis that Integrin signaling promotes directed cardiomyocyte migration by establishing an organized, polarized epithelium; Aim 2 - Determine the role of Integrins in ventricle development. This aim combines cardiomyocyte number quantification and temporal differentiation assays to test the hypothesis that Integrins drive heart growth by promoting addition of later- differentiating second heart field (SHF) cardiomyocytes to the ventricle and outflow tract; Aim 3 - Determine the tissue-specific and temporal requirements for Integrins in promoting cardiomyocyte migration and SHF addition. This aim uses novel transgenic lines to spatially and temporally regulate Integrin expression to test the hypothesis that Integrin signaling acts specifically in the cardiomyocytes, first to promote cardiomyocyte migration, and later to promote second heart field addition. By illuminating how different cardiomyocyte populations integrate and interpret signals from the surrounding ECM, our results may provide insight into the etiology of CHDs in humans, and can be applied to novel tissue engineering therapies aimed at restoring efficient heart function.

概括 适当的心脏发育对于终生有效的心脏功能至关重要。先天性心脏 缺陷 (CHD) 是最常见的先天畸形，发生率高达 1% 的活产儿和 10% 的婴儿 仍然出生。先心病还会导致成人患心血管疾病的风险增加。脊椎动物心脏期间 发育过程中，心肌祖细胞被丰富的细胞外基质（ECM）包围。突变在 人体中的几种 ECM 蛋白可导致先心病 (CHD)。然而，CHD 的相关机制 影响 ECM 的突变仍知之甚少。来自 ECM 的信号由整合素检测 靶细胞上的受体。我们对斑马鱼携带功能丧失突变的初步分析 整合素α5和整合素α4基因表明，这些整合素是反复需要促进 适当的心脏形态发生和心室大小。该提案的总体目标是阐明机制 心肌细胞通过它解释和整合来自 ECM 的信号以执行适当的心肌细胞操作 迁移和心脏生长。该提案的具体目标是： 目标 1 - 确定机制 整合素信号介导适当的心肌细胞迁移。这一目标将使用组织学技术和 对活胚胎进行共焦延时显微镜检查，以检验整合素信号传导促进定向的假设 通过建立有组织的极化上皮来实现心肌细胞迁移；目标 2 - 确定角色 心室发育中的整合素。该目标结合了心肌细胞数量定量和时间 分化测定来检验整合素通过促进后期添加来驱动心脏生长的假设 将第二心区 (SHF) 心肌细胞分化为心室和流出道；目标 3 - 确定 整合素促进心肌细胞迁移和 SHF 的组织特异性和时间需求 添加。该目标使用新型转基因系在空间和时间上调节整合素表达来测试 整合素信号传导在心肌细胞中特异性作用，首先促进心肌细胞的假设 迁移，后期促进第二心田加成。通过阐明心肌细胞如何不同 人群整合并解释来自周围 ECM 的信号，我们的结果可以提供对 人类冠心病的病因学，可应用于旨在恢复健康的新型组织工程疗法 有效的心脏功能。