CARDIOVASCULAR REMODELING MEDIATED BY RXRa RECEPTORS

RXRa 受体介导的心血管重塑

• 批准号: 6499014
• 负责人: STEVEN W KUBALAK
• 金额: $ 24.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-02 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499014
• 关键词: apoptosis; calcium channel; cardiogenesis; cell proliferation; congenital heart disorder; embryo /fetus; genetically modified animals; heart; histogenesis; laboratory mouse; mammalian embryology; receptor expression; transforming growth factors

Cardiovascular defects associated with the formation and remodeling of endocardial cushion tissue accounts for a large proportion of congenital heart disease in the United States each year [1.2]. The molecular mechanisms integrating the processes of proliferation, differentiation, and apoptosis for proper remodeling of the tubular heart to form the four- chambered organ is not clear. The complex processes associated with remodeling of endocardial cushion tissue into valvular structures involves multiple cell lineages of myocardial, endothelial, mesenchymal, neural crest, and epicardial origins. Remodeling events such as epithelial-to- mesenchymal transformation to cushion tissue and myocardialization in the outflow tract and atrioventricular canal are the result of a precise coordination of these processes. The retinoid X-receptor alpha knockout (RXRalpha-KO) mouse model shows considerable promise at clarifying these relationships and aiding in the determination of the causes of congenital heart defects. At embryonic day (E) 13.5, RXRalpha-KO embryos display a spectrum of endocardial fusion tissue and ventricular chamber malformations analogous to human congenital heart defects [3.5]. Preliminary evidence indicates there is a reduced proliferation and increased apoptosis in RXRalpha-KO embryonic hearts. Moreover,, in RXRalpha-KO embryos, we found elevated levels of TGF-beta2 mRNA and protein in the heart. Thus, our hypothesis is that RXRalpha functions to integrate the processes of proliferation, differentiation, and apoptosis during remodeling of cushion tissue in the outflow tract, AV canal, and ventricular myocardium and that TGF-beta2 contributes to these processes in an RXRalpha-dependent manner. The Specific Aims of this proposal are: 1) To test the hypothesis that epithelial-to-mesenchymal cell transformation in the conotruncal and atrioventricular cushions is RXRalpha-dependent. II) To determine the role of RXRalpha in the processes of proliferation and apoptosis during septation of the conotruncus and ventricular chambers. III) To test the hypothesis that disruption of RXRalpha expression during cardiogenesis results in cardiac defects that are TGFbeta2 dependent.

在美国，每年与心内膜垫组织形成和重塑相关的心血管缺陷在先天性心脏病中占很大比例[1.2]。整合增殖、分化和凋亡过程以正确重塑管状心脏形成四室器官的分子机制尚不清楚。与心内膜垫组织重塑为瓣膜结构相关的复杂过程涉及心肌、内皮、间质、神经嵴和心外膜起源的多个细胞谱系。诸如上皮间质转化为缓冲组织以及流出道和房室管中的心肌化等重塑事件是这些过程精确协调的结果。视黄醇 X 受体 α 敲除 (RXRalpha-KO) 小鼠模型在阐明这些关系并帮助确定先天性心脏缺陷的原因方面显示出巨大的前景。在胚胎第 (E) 13.5 天，RXRalpha-KO 胚胎表现出一系列心内膜融合组织和心室畸形，类似于人类先天性心脏缺陷 [3.5]。初步证据表明 RXRalpha-KO 胚胎心脏增殖减少，细胞凋亡增加。此外，在 RXRalpha-KO 胚胎中，我们发现心脏中 TGF-β2 mRNA 和蛋白质的水平升高。因此，我们的假设是，RXRα 在流出道、AV 管和心室心肌的垫层组织重塑过程中发挥整合增殖、分化和凋亡过程的作用，并且 TGF-β2 以 RXRα 依赖性方式参与这些过程。该提案的具体目标是： 1) 检验圆锥干和房室垫中的上皮细胞向间质细胞转化是 RXRα 依赖性的假设。 II)确定RXRα在圆锥干和心室分隔过程中增殖和凋亡过程中的作用。 III) 检验以下假设：心脏发生过程中 RXRalpha 表达的破坏会导致 TGFbeta2 依赖性心脏缺陷。