Cspg2 Gene and Cardiac Outlet Morphogenesis

Cspg2 基因和心脏出口形态发生

• 批准号: 6537933
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537933
• 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 无效胚胎提供了显著的证据，表明Cspg 2基因（多功能蛋白聚糖） 在出口的生长和分化中发挥了意想不到的重要作用， 心脏的一部分（圆锥干）。我们建议确定 在一个地区，这是一个“热点”的临床重要的生产 这些缺陷影响了超过一半的人类活产心脏缺陷。的 发育中的出口的圆锥干形成于以前未被认识的 位于原始心室前面的中胚层心脏区域。我们 提出Cspg 2基因促进细胞的分化和稳定， 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）特定的功能域， Cspg 2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丢失 Cspg 2的特异性功能结构域的缺失导致了这些阶段的出现。一个 多功能蛋白聚糖表达的早期异常丢失或其他变化 招募或后期重塑阶段，影响正常的模式， 表型稳定的干心肌，并导致圆锥动脉干 心脏缺陷我们提出以下具体目标：1）确定 Cspg 2功能域在发育中的圆锥干中的表达模式 在（a）心肌从前心野的早期募集期间 中胚层（AHF）和在（B）后期，当知道干心肌时 2）为了检验Cspg 2起稳定细胞的作用的假设， 通过在整个转基因动物中过表达Cspg 2来获得芋头干细胞表型 老鼠模型。3)确定是否需要特定的Cspg 2功能域 用于圆锥干心肌的募集和/或稳定 收缩和诱导信号表型; 4）确定是否特异性 Cspg 2蛋白的结构域在以后的皮质神经元中具有功能性作用。 通过使心肌不稳定来重塑动脉干， 转分化成纤维结缔组织。