FUNCTION OF CX43-INTERACTING PROTEINS IN NEURAL CREST MIGRATION

CX43 相互作用蛋白在神经嵴迁移中的功能

基本信息

批准号：
7157004
负责人：
ROBERT G GOURDIE
金额：
$ 35.44万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7157004
关键词：
Actin-Binding Protein Actins Adenoviruses Adherent Culture Affect Authorization documentation Behavior Binding C-terminal Cardiac Cardiovascular system Cells Characteristics Chick Embryo Complementary DNA Computer Systems Development Congenital Abnormality Connexin 43 Connexins Coupling Cytoskeleton Data Development Drosophila genus Embryo Ensure Epithelial Cells FGF8 gene Fibroblast Growth Factor 8 Fibroblasts Gap Junctions Grant Green Fluorescent Proteins Heart Homocysteine Homocystine Human Immigration In Vitro Mediating Migration Assay Molecular Morphogenesis Mus Myocardial N-terminal NIH 3T3 Cells Neural Crest Neural Crest Cell Neural tube PDZ protein Pattern Peptides Principal Investigator Protein Binding Proteins Publishing Rate Regulation Reporting Resources Role Testing Transgenic Mice Translations Tumor Suppressor Proteins United States National Institutes of Health Work base cardiogenesis cell motility cell type concept design driving force in vivo insight migration mouse model mutant novel programs tool wound

项目摘要

DESCRIPTION (provided by applicant): Proper coordination of neural crest migration is an absolute requirement for normal cardiovascular development - most particularly outflow tract morphogenesis. The gap junction protein Cx43 has a key function in this directed migration of cardiac neural crest cells. The molecular mechanism by which Cx43 affects neural crest motility is unknown. The forces driving cell migration are generated largely by the dynamics of the actin cytoskeleton. We hypothesize that proteins mediating linkage between connexins and actin are candidates for regulators of cell motility. One molecule known to mediate interaction between connexins and actin is ZO1 - a PDZ protein related to the Drosophila tumor suppressor protein discs large. The Gourdie lab has shown that Cx43-ZO1 interaction is critical to developmental remodeling of the extent of gap junctional contact between myocardial cells. Furthermore, we have data showing that inhibition of ZO1- Cx43 interaction decreases neural crest outgrowth in vitro and reduces motility of fibroblasts and epithelial cells in cultured monolayers in a "scratch wound" migration assay. We will test the hypothesis that ZO1-Cx43 interaction is an integral part of a mechanism involved in regulation of cell-cell contact pattern and migration of neural crest cells by determining: 1. Whether factors known to stimulate neural crest cell motility, affect interactions between Cx43, ZO-1 and other connexin interacting proteins in vitro; 2. Whether inhibition of ZO1-Cx43 interaction is sufficient to disrupt regulation of the rate and directionality of neural crest cell migration in vitro; and 3. if ZO1-Cx43 interaction is necessary for the directed migration of neural crest cells in vivo. This study will provide new insight into molecular regulation of neural crest migration in the embryo and origins of birth defects in humans.

描述（由申请人提供）：神经rest迁移的适当协调是正常心血管发育的绝对要求 - 尤其是流出道的形态发生。间隙连接蛋白CX43在心脏神经rest细胞的定向迁移中具有关键功能。 CX43影响神经Crest运动的分子机制尚不清楚。驱动细胞迁移的力主要由肌动蛋白细胞骨架的动力学产生。我们假设介导连接素和肌动蛋白之间连接的蛋白质是细胞运动调节剂的候选者。一种已知可以介导连接蛋白与肌动蛋白之间相互作用的分子是ZO1-一种与果蝇抑制蛋白蛋白盘相关的PDZ蛋白。 Gourdie Lab表明，CX43-ZO1相互作用对于心肌细胞之间间隙连接范围接触程度的发育重塑至关重要。此外，我们还有数据表明，ZO1-CX43相互作用的抑制可降低体外神经rest的生长，并降低培养的单层中培养的单层中成纤维细胞和上皮细胞的运动性。我们将检验以下假设：ZO1-CX43相互作用是通过确定：1。是否已知的因素刺激神经Crest细胞运动的因素，影响细胞 - 细胞接触模式和神经Crest细胞的迁移的机制不可或缺的一部分CX43，ZO-1和其他连接蛋白在体外相互作用； 2。抑制ZO1-CX43相互作用是否足以破坏体外神经Crest细胞迁移的速率和方向性的调节； 3。如果ZO1-CX43相互作用对于体内神经Crest细胞的定向迁移是必需的。这项研究将为人类的胚胎和出生缺陷的起源神经rest迁移的分子调节提供新的见解。