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Molecular mechanisms of tissue interactions during coronal suture development

冠状缝发育过程中组织相互作用的分子机制

基本信息

批准号：
10663822
负责人：
Fenglei He
金额：
$ 35.77万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663822
关键词：
Ablation Adult Attention Brain Calvaria Cell Communication Cell Maintenance Cells Chondrocytes Congenital Abnormality Craniofacial Abnormalities Craniosynostosis Data Defect Development Diagnosis Embryonic Development Excision Face Frontal bone structure Genetic Genetic Transcription Genetically Engineered Mouse Goals Growth Homeostasis Human Injury Knowledge Maintenance Mediator Mesenchymal Stem Cells Modeling Molecular Mutation Operative Surgical Procedures PDGFRA gene Parietal bone structure Pathway interactions Patients Phenotype Play Regulation Research Research Personnel Role Signal Transduction Site Surgical sutures Tectum Mesencephali Testing Tissues WNT9A gene beta catenin bone coronal suture craniofacial development gain of function insight loss of function mouse model new therapeutic target novel novel therapeutic intervention premature progenitor stem cell biomarkers stem cells therapeutically effective tool transcriptomic profiling

项目摘要

The overall objective in this application is to examine the fundamental mechanisms underlying coronal suture development. We will test the central hypothesis that tissue interaction between tectum transversum (TTR) and coronal sutures interact during development, and a rigorous regulation of Pdgfra activity is required for their interaction. Pdgfra plays a crucial role in craniofacial development, and elevated PDGFRA expression and activity is implicated in human craniosynostosis. We will examine the following specific aims: 1. To examine interaction between TTR and suture cells during embryonic development. In this aim we will test the hypothesis that TTR and suture cells interact during embryogenesis. In aim 1a, we will examine the coronal suture development with removal of TTR. In aim 1b, we will assess the requirement of coronal sutures on TTR development. We will use genetic tools to ablate coronal sutures specifically and assess TTR development in mouse models. 2. To examine the mechanisms underlying Pdgfra regulation on TTR development. The regulatory mechanisms underlying TTR development has not been illustrated. Alteration of Pdgfra activity causes distinct TTR phenotype, indicating Pdgfra is a critical player in TTR formation. By transcriptome profiling we identified Wnt9a and Sox9 as transcriptional targets of Pdgfra. In this aim we will test the hypothesis that Pdgfra regulates chondrocyte progenitors formation by regulating Sox9 expression via Wnt9a/beta-catenin signaling. In aim 2a, we will characterize the role of Pdgfra in TTR development, by analyzing the TTR phenotype in both Pdgfra loss-of-function (LOF) and gain-of-function (GOF) models. In aim 2b, we will analyze the role of Pdgfra in controlling chondrocyte progenitor formation. In aim 2c, we will examine Wnt9a/beta-catenin pathway as a potential mediator of Pdgfra in controlling Sox9 expression and chondrocyte progenitor formation. 3. To examine the role of Pdgfra in coronal sutural cells development and maintenance. It has been shown that suture contains abundant mesenchymal stem cells (MSCs). Pdgfra is a recognized MSCs marker. Our data show that Pdgfra is expressed in the developing suture. Constitutive activation of Pdgfra leads to abnormal differentiation in the developing sutures. In aim 3a, we will trace the suture progenitor cells in both Pdgfra LOF and GOF models by manipulating Pdgfra activity in a tissue-specific manner. In aim 3b, we will examine the role for Pdgfra in adult suture MSCs maintenance and their homeostasis using calvarial injury model. By completion of the proposed study, we expect to answer whether tissue interaction between TTR and coronal suture is essential for normal suture development, and what is the specific role for Pdgfra in normal suture development and craniosynostosis formation.

本应用程序的总体目标是研究日冕物质抛射的基本机制，缝线发育。我们将检验中心假设，即横盖之间的组织相互作用 (TTR)和冠状缝在发育过程中相互作用，需要对Pdgfra活性进行严格的调节为了他们的互动。PDGFRA在颅面发育中起着至关重要的作用，和活动与人类颅缝早闭症有关。我们将研究以下具体目标： 1.探讨胚胎发育过程中TTR与缝细胞的相互作用。在这个目标中，我们将测试的假设，TTR和缝合细胞在胚胎发生过程中相互作用。在目标1a中，我们将检查去除TTR后冠状缝的发育情况。在目标1b中，我们将评估冠状缝对TTR发育的影响。我们将使用基因工具来切除冠状缝，评估小鼠模型中TTR的发展。 2.研究Pdgfra调控TTR发育的潜在机制。 TTR发展的调控机制尚未阐明。Pdgfra活性的改变导致不同的TTR表型，表明Pdgfra是TTR形成的关键因素。通过转录组我们鉴定了Wnt 9a和Sox 9作为Pdgfra的转录靶标。为此，我们将测试 Pdgfra通过调节Sox 9表达调节软骨祖细胞形成的假说， Wnt 9a/β-连环蛋白信号传导。在目标2a中，我们将描述Pdgfra在TTR开发中的作用，分析Pdgfra功能丧失（LOF）和功能获得（GOF）模型中的TTR表型。在aim中 2b，我们将分析Pdgfra在控制软骨细胞祖细胞形成中的作用。在目标2c中，我们将检查Wnt 9a/β-连环蛋白途径作为Pdgfra在控制Sox 9表达中的潜在介导物，软骨细胞祖细胞形成。 3.目的：研究Pdgfra在冠状缝细胞发育和维持中的作用。研究表明，缝线中含有丰富的间充质干细胞（MSCs）。PDGFRA是公认的 MSCs标记物。我们的数据显示Pdgfra在发育中的缝合中表达。的组成性激活 Pdgfra导致发育缝的异常分化。在aim 3a中，我们将追踪缝线 Pdgfra LOF和GOF模型中的祖细胞，通过操纵组织特异性方式在目的3b中，我们将检查Pdgfra在成体缝合MSC维持中的作用及其在成骨细胞中的表达。使用颅骨损伤模型的内稳态。通过完成拟议的研究，我们希望回答TTR和冠状缝对于正常缝的发育是必不可少的，Pdgfra在正常缝中的具体作用是什么？缝发育和颅缝早闭形成。