Molecular Interactions During Neural Crest Formation

神经嵴形成过程中的分子相互作用

基本信息

批准号：
9536336
负责人：
MARTIN I. GARCIA-CASTRO
金额：
$ 10.58万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-04 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9536336
关键词：
Address Animal Model Binding Biological Assay Biology Birds Cartilage Cell model Cells Chick Embryo DUSP6 protein Data Defect Derivation procedure Development Diagnostic Disease Electroporation Embryo Endothelin Epiblast Erinaceidae Event Face Family Feedback Fibroblast Growth Factor Gastrula Gene Expression Genetic Transcription Goals Homeostasis Human Human Development Human Pathology Laboratories Lateral Malignant Neoplasms Mammals Modeling Molecular Monitor Muscle Neural Crest Neural Crest Cell PEA3 Pathway interactions Peripheral Nervous System Phase Population Publishing Role Signal Pathway Signal Transduction Skin Syndrome TCF Transcription Factor Testing Therapeutic Time Translations Tretinoin Vertebrates WNT Signaling Pathway Waardenburg syndrome Work base blastocyst cleft lip and palate craniofacial cranium gastrulation human embryonic stem cell human stem cells inhibitor/antagonist knock-down malformation melanocyte melanoma neural plate neurodevelopment neuroregulation notch protein novel prospective public health relevance receptor response transcription factor

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this project is to advance our understanding of the cellular and molecular mechanisms that control neural crest development. Neural crest cells are vertebrate-specific, appear early in development, migrate extensively and differentiate into several derivatives, including: craniofacial components (muscle and cartilage amongst others), peripheral nervous system and melanocytes of the skin. Defects in neural crest development and homeostasis result in human pathologies known as "neurocristopathies" that include cleft lip/palate, Waardenburg syndrome, and melanoma, amongst others. Advancing our understanding of the biology of neural crest cells is fundamental to aid in diagnostic and therapeutic approaches. This project investigates early stages of neural crest formation, and focuses on the contributions made by signaling pathways. This work centers in two models - the avian embryo and a novel model of human neural crest development based on human embryonic stem cells. In the chick we utilize blastula embryos, while in the human stem cell model we address the earliest time points of differentiation. In both models, the role of Wnt and FGF signaling pathways will be scrutinized with particular focus on transcriptional effectors. Aim 1 is directed to elucidate the specific contributions made by distinct FGF-signaling branches during blastula and gastrula stages, and to establish differential responses and transcriptional effectors of the Pea3 sub-family. Aim 2 dissects the contributions made by the dominant canonical and alternative non- canonical Wnt pathways. Here emphasis will be directed to the transcriptional factors Tcf and Lef. Aim 3 will validate and eficcient model of human NC development, and establish the contributions made by these two signaling pathways (FGF, Wnt) to human neural crest development using an efficient and robust model based in human embryonic stem cells. This work will illuminate fundamental principles of neural crest formation in higher vertebrates (birds and mammals), and will invigorate human neural crest studies.

描述（由申请人提供）：该项目的长期目标是促进我们对控制神经rest发育的细胞和分子机制的理解。神经rest细胞是脊椎动物特异性的，出现在发育的早期，广泛地迁移并分化为多种衍生物，包括：颅面成分（肌肉和软骨等），外周神经系统和皮肤的黑素细胞。神经rest发育和稳态的缺陷导致人类病理被称为“神经抗化性”，其中包括唇lip/papleate，Waardenburg综合征和黑色素瘤等。促进我们对神经rest细胞生物学的理解是有助于诊断和治疗方法的基础。该项目研究了神经rest形成的早期阶段，并重点介绍了信号通路所做的贡献。这项工作以两个模型为中心 - 基于人类胚胎干细胞的人类神经rest发育的新型模型。在小鸡中，我们利用胚胎胚胎，而在人类干细胞模型中，我们解决了分化的最早时间点。在这两个模型中，Wnt和FGF信号通路的作用将被仔细检查，特别关注转录效应子。 AIM 1旨在阐明在囊泡和胃阶段在不同的FGF信号分支中做出的特定贡献，并建立PEA3子家庭的差异响应和转录效应子。 AIM 2剖析了主要的规范和替代非规范WNT途径所做的贡献。这里的重点将针对转录因子TCF和LEF。 AIM 3将验证人类NC发育的效果模型，并建立这两种信号通路（FGF，WNT）对人类神经rest发育的贡献，该模型使用基于人类胚胎干细胞的有效且可靠的模型。这项工作将阐明高脊椎动物（鸟类和哺乳动物）中神经rest形成的基本原理，并会激发人类神经rest研究。