Cspg2 Gene and Cardiac Outlet Morphogenesis

Cspg2 基因和心脏出口形态发生

• 批准号: 6638724
• 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/6638724
• 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(申请人提供)：我们对心脏缺陷(HDF)的观察 零胚胎提供了Cspg2基因(Versican)具有 在奥特莱斯的成长和差异化中发挥着意想不到的重要作用 心脏的一段(圆锥干)。我们建议确定关键角色 在一个临床上重要分娩的“热点”地区 心脏缺陷影响了超过一半的人类先天心脏缺陷。这个 发展中的出口的圆锥主干形成于以前未被识别的 中胚层心场位于原始脑室前方。我们 提示Cspg2基因可促进肿瘤细胞的分化和稳定 心肌作为收缩和诱导信号组织的表型 生长着的圆锥树干。我们的假设是1)特定的功能域 Cspg2是生长中的心脏出口正常心肌募集所必需的 2)晚期重塑时干心肌的程序性丢失 阶段是由于Cspg2缺乏特定的功能结构域而导致的。一个 变态表达在早期的异常丧失或其他变异 募集或后期重塑阶段，影响正常的模式 心肌干的表型稳定化和圆锥干的形成 心脏缺陷。我们提出以下具体目标：1)确定 Cspg2功能结构域在发育圆锥中的表达模式 在(A)心脏前区早期心肌复张过程中 中胚层(AHF)和(B)已知干心肌的后期 以回归；2)检验Cspg2功能稳定的假设 Cspg2基因在整个动物体内过表达的圆锥体表型 小鼠模型；3)确定是否需要特定的Cspg2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)确定特异性 Cspg2蛋白的结构域后来在顶端发挥了功能作用 通过使心肌不稳定来重塑主干的研究进展 转分化为纤维结缔组织。