MYOCARDIALIZATION AND EPICARDIALIZATION OF CUSHION TISSUE

垫层组织的心肌化和心外膜化

• 批准号: 6564954
• 负责人: Andy Wessels
• 金额: $ 19.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564954
• 关键词: cell cell interaction; cell differentiation; cell migration; cell proliferation; cell transformation; congenital heart disorder; embryo /fetus tissue /cell culture; endocardium; genetic strain; heart valves; histogenesis; laboratory mouse; mammalian embryology; mesenchyme; myocardium

The formation of septa and valves in the developing heart are crucial morphogenetic events that allow the initially single, embryonic cardiac tube to develop into a complex 4-chambered heart, supporting two different blood circulations. This development involves remodeling of the endocardial cushions, and (2) epicardialization, the migration of epicardially derived cells into the cushion tissues. Preliminary data indicate that perturbation of either process can lead to cardiac malformations involving the developing outflow tract (OFT) and atrioventricular (AV) function. The studies proposed in AIM 1 of this project are designed to address the overall working hypothesis that myocardialization is the "driving force" of segmental and septal alignment of the AV junction. The specific goals in this aim are (1) to elucidate the role of TGFbeta in the regulation of myocardialization and to test the hypothesis that perturbation TGFbeta signaling pathways in the outflow tract will lead to perturbation of myocardialization resulting in a specific set of congenital malformations including double outlet right ventricle (DORV) and double inlet left ventricle (DILV), and (2) to describe the myocardialization-induced remodeling of the linear curvature leading to the rightward expansion of the atrioventricular canal resulting in the connection between right atrium and right ventricle. The studies proposed in AIM 2 of this application focus on the role of epicardial derived cells (EPDCs) in valvuloseptal morphogenesis. The central working hypothesis here is that EPDCs play a crucial role in the regulation of mesenchymal cell transformation, proliferation, and differentiation of the endocardial cushions. The specific goals to be studied are (1) to test the hypothesis that proper development of the atrioventricular valves relies on timely regulated immigration of EPDCs into the endocardial cushion tissues, and (2) to test the hypothesis that EPDCs regulate endocardial cushion formation by local inhibition of endocardial-to-mesenchymal cell transformation and proliferation, and by promotion of differentiation. Pursuit of these aims will further advance our knowledge of the molecular and cellular events that underlie normal cardiac development, and will lead to new insights in the processes that can cause congenital heart disease and the role of the cushion tissues therein.

发育中的心脏中隔膜和瓣膜的形成是至关重要的形态发生事件，使最初的单个胚胎心管发育成复杂的四腔心脏，支持两种不同的血液循环。这一发展涉及心内膜垫的重塑，以及（2）心外膜化，即心外膜来源的细胞迁移到垫组织中。初步数据表明，任何一个过程的扰动都可能导致涉及发育中的流出道（OFT）和房室（AV）功能的心脏畸形。该项目 AIM 1 中提出的研究旨在解决总体工作假设，即心肌化是 AV 交界节段和间隔对齐的“驱动力”。该目标的具体目标是 (1) 阐明 TGFbeta 在心肌化调节中的作用，并检验以下假设：扰动流出道中的 TGFbeta 信号通路将导致心肌化扰动，从而导致一系列特定的先天畸形，包括右心室双出口 (DORV) 和左心室双入口 (DILV)，以及 (2) 描述心肌化引起的线性曲率重塑，导致向右扩张房室管连接右心房和右心室。本申请的 AIM 2 中提出的研究重点关注心外膜衍生细胞 (EPDC) 在瓣膜间隔形态发生中的作用。这里的核心工作假设是 EPDC 在调节间充质细胞转化、增殖和心内膜垫分化中发挥着至关重要的作用。要研究的具体目标是（1）检验房室瓣的正常发育依赖于 EPDC 及时调节迁移到心内膜垫组织的假设，以及（2）检验 EPDC 通过局部调节心内膜垫形成的假设。抑制心内膜到间质细胞的转化和增殖，并促进分化。对这些目标的追求将进一步增进我们对正常心脏发育基础的分子和细胞事件的了解，并将导致对导致先天性心脏病的过程以及缓冲组织在其中的作用的新见解。