Cell-ECM interactions in the development of the aortic arch arteries

主动脉弓发育中的细胞-ECM 相互作用

基本信息

批准号：
9484520
负责人：
Sophie Astrof
金额：
$ 4.14万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9484520
关键词：
Actins Address Alpha Cell Alternative Splicing Arteries Biological Biomechanics Blood Blood Vessels Branchial arch structure Cardiac Cardiovascular system Cell Culture Techniques Cell Differentiation Induction Cell Differentiation process Cell Nucleus Cells Communication Complement Complement Factor B Congenital Abnormality Cytoplasm Cytoskeleton Data Defect Development Embryo Embryonic Development Endothelium Exons Extracellular Matrix Fibronectins Frequencies Genes Genetic Transcription Glycoproteins Grant Heart Human Hydrogels Impairment In Situ Hybridization In Vitro Integrin alpha5 Integrin alpha5beta1 Integrins Interruption Life Live Birth MADH2 gene Mechanics Mediating Messenger RNA Modeling Molecular Molecular Genetics Morbidity - disease rate Morphogenesis Mouse Strains Mus Muscle Cells Mutagenesis Neonatal Neural Crest Neural Crest Cell Nuclear Nuclear Translocation Operative Surgical Procedures Pathway interactions Patients Pattern Pharmacology Play Process Proteins RNA Splicing Rest Role Signal Transduction Smooth Muscle Source Stem cells System Testing Tissues Transforming Growth Factor beta Trees Variant Vascular Smooth Muscle aortic arch cell motility cell type chemical property congenital heart disorder embryo tissue experimental study in vivo insight mechanical properties mortality mutant myocardin polymerization progenitor public health relevance receptor transcription factor

项目摘要

DESCRIPTION (provided by applicant): Embryonic morphogenesis requires coordinated communications among diverse cell types. Dysregulation of these interactions results in birth defects. Signaling among cells in vivo occurs in the context of the extracellular matrix (ECM), and both the chemical and mechanical properties of the ECM regulate cell signaling and progenitor cell fates. Mechanisms whereby components of the ECM regulate embryonic morphogenesis are not well understood. In the course of the studies supported by our first R01, we made the intriguing discovery that synthesis of the ECM glycoprotein fibronectin (Fn1) is dynamically regulated during mouse embryonic development, and that the expression of Fn1 is highly enriched in distinct embryonic progenitors important for cardiovascular morphogenesis. Fn1 is a highly conserved vertebrate glycoprotein encoded by a single gene in mice and humans, and previous studies showed that Fn1 is required for cardiovascular development. Therefore, we hypothesized that different cellular sources of Fn1 played distinct, biologically significant roles in the development of the cardiovascular system. Preliminary data presented in this grant demonstrate that Fn1 synthesized by the neural crest (NC) is essential for the development of the aortic arch arteries (AAAs), a system of blood vessels that routs oxygenated blood from the heart to the rest of the body. Fn1 mRNA and protein become highly induced in NC cells surrounding the pharyngeal arch arteries as these blood vessels mature into the AAAs, and we show that Fn1 synthesized by NC cells around the pharyngeal arch arteries regulates the differentiation of NC cells into vascular smooth muscle cells (VSMCs). We present evidence suggesting that Fn1 synthesized by the NC regulates NC-to-VSMC differentiation in a cell- autonomous manner by signaling through integrin α5β1 and regulating actin polymerization, which in turn, regulates the translocation of the myocardin-related transcription factor B (MRTFB) from the cytoplasm into the nucleus. In the nucleus, MRTFB can directly activate the transcription of smooth muscle genes, and we show that a deletion mutant of MRTFB that constitutively localizes to the nucleus rescues smooth muscle differentiation in Fn1-deficient NC cells. In this renewal application we propose to determine the mechanisms by which Fn1 regulates NC-to-VSMC differentiation and the role of tissue biomechanics in this process by addressing the following Specific Aims: 1) To test the hypothesis that Fn1 regulates the differentiation of NC cells into VSMCs by signaling through integrin α5β1; 2) To test the hypothesis that Fn1 and tissue biomechanics regulate NC-to-VSMC differentiation by modulating actin cytoskeletal dynamics and nuclear localization of MRTFB; and 3) To test the hypotheses that EIIIA+ and EIIIB+ forms of Fn1 regulate NC-to-VSMC differentiation and that the induction of Fn1 in NC cells surrounding the endothelium of the pharyngeal arch arteries is mediated by SMAD2-dependent signaling.

描述（通过应用程序）：胚胎细胞类型之间的胚胎形态发生，导致了ECM常规和祖细胞命运的Hanical缺陷。 ECM糖蛋白的合成（纤连蛋白（FN1）在小鼠胚胎发育过程中是定制的。心血管形态发生的载体。IES表明，FN1是心血管发育所必需的。我们假设FN1在FN1中起着不同的细胞来源，这是FN1所必需的。心血管系统。表明FN1在咽古细胞周围综合了Thas，调节了NC细胞向沿沿肌肉平滑肌细胞的区分（VSMC）。通过整合素1和调节肌动蛋白相关转录因子B（MRTFB）的肌动蛋白聚合的信号传导，从细胞质中进入细胞核，MRTFB可以直接激活平滑肌基因的转录核营救了FN1-DEF图NC细胞中的肌肉分化。通过信号整合蛋白α5β1来测试假设FN1通过SIGNC的分化为VSMC，以测试FN1和组织生物力学NC-TO-VSMC通过调节肌动蛋白细胞骨骼动力学和MRTFB的核电的假设假设FN1常规NC-TO-VSMC差异的EIIA+和EIIIB+形式的假设以及对伴侣动脉内皮的NC细胞中FN1的指示是由Smad2-Dependepentententententententententententententents介导的。