Cspg2 Gene and Cardiac Outlet Morphogenesis

Cspg2 基因和心脏出口形态发生

• 批准号: 6399586
• 负责人: COREY H MJAATVEDT
• 金额: $ 28.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399586
• 关键词: congenital heart disorder; developmental genetics; embryogenesis; genetically modified animals; heart; histogenesis; laboratory mouse; mammalian embryology; mesoderm; myocardium

DESCRIPTION (provided by applicant): Our observations of the heart defect (hdf) null embryo has provided remarkable evidence that the Cspg2 gene (versican) has an unexpectedly important role in the growth and differentiation of the outlet segment (conotruncus) of the heart. We propose to determine the critical role of versican in a region that is a "hot spot" for clinically important birth defects affecting over one-half of all human live birth heart defects. The conotruncus of the developing outlet forms from a previously unrecognized mesodermal heart field located anteriorly to the primitive ventricle. We propose the Cspg2 gene promotes differentiation and stabilization of the myocardial phenotype as a contractile and inductive signaling tissue in the growing conotruncus. Our hypothesis is that 1) specific functional domains of Cspg2 are required for normal myocardial recruitment in the growing outlet and 2) the programmed loss of the truncus myocardium during the late remodeling stages results from the absence of specific functional domains of Cspg2. An abnormal loss or other variation of versican expression at the early recruitment or later remodeling stages, affects the normal patterns of phenotypic stabilization in the truncus myocardium and results in conotruncal heart defects. We propose the following Specific Aims: 1) To determine the expression patterns of Cspg2 functional domains in the developing conotruncus during (a) early recruitment of the myocardium from the anterior heart field mesoderm (AHF) and during (b) later stages when the truncal myocardium is known to regress; 2) To test the hypothesis that Cspg2 functions to stabilize the conotruncus phenotype by overexpressing Cspg2 in a whole animal transgenic mouse model.; 3) To determine if specific Cspg2 functional domains are required for recruitment and/or stabilization of the conotruncus myocardium's contractile and inductive signalling phenotypes; 4) To determine if specific domains of the Cspg2 protein have a functional role later in contruncal development to remodel the truncus by destabilizing the myocardium for transdifferentiation into a fibrous connective tissue.

描述（由申请人提供）：我们对心脏缺陷（hdf）的观察 无效胚胎提供了显着的证据表明 Cspg2 基因（versican） 在门店的成长和差异化中发挥了意想不到的重要作用 心脏的节段（圆锥干）。我们建议确定关键角色 多功能蛋白聚糖位于临床重要分娩“热点”区域 影响超过一半的人类活产心脏缺陷。这 圆锥干的发展出口形式从以前未被认识到 中胚层心区位于原始心室前面。我们 提出Cspg2基因促进分化和稳定 心肌表型作为收缩和诱导信号组织 生长的圆锥干。我们的假设是 1) 的特定功能域 Cspg2 是生长出口正常心肌募集所必需的 2）晚期重构过程中心肌干的程序性损失 阶段是由于 Cspg2 特定功能域的缺失造成的。一个 早期多功能蛋白聚糖表达的异常丢失或其他变异 招募或后期重塑阶段，影响正常模式 心肌干的表型稳定并导致圆锥干 心脏缺陷。我们提出以下具体目标： 1) 确定 发育中圆锥干中 Cspg2 功能域的表达模式 (a) 早期从前心区募集心肌期间 中胚层 (AHF) 和 (b) 后期（当躯干心肌已知时） 倒退； 2）检验Cspg2功能稳定的假设 通过在整个转基因动物中过表达 Cspg2 来观察圆锥断干表型 鼠标模型。； 3) 确定是否需要特定的Cspg2功能域 用于募集和/或稳定圆锥干心肌 收缩和感应信号表型； 4）确定是否具体 Cspg2 蛋白的结构域在随后的肿瘤细胞中发挥功能作用 通过破坏心肌的稳定性来重塑动脉干 转分化为纤维结缔组织。