Characterizing the cranial neural crest response to BMP signaling through gastrulation and neurulation

通过原肠胚形成和神经形成表征颅神经嵴对 BMP 信号的反应

基本信息

批准号：
10782064
负责人：
Michael Louis Piacentino
金额：
$ 24.9万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10782064
关键词：
Binding Biology CHARGE syndrome California Cartilage Cells Cephalic Chick Childhood Cleft Palate Clustered Regularly Interspaced Short Palindromic Repeats Congenital Abnormality Craniofacial Abnormalities Data Set Defect Dentin Development DiGeorge Syndrome Diffusion Ectoderm Embryo Environment Epidermis Event Face Ganglia Gastrula Genes Genetic Epistasis Goals Image Individual Inhibitor of Differentiation Proteins Lateral Lead Ligands Mandibulofacial Dysostosis Measures Medial Mentors Molecular Neural Crest Neural Crest Cell Pathway interactions Peptide Hydrolases Peripheral Peripheral Nervous System Phase Play Population Reaction Regulation Reporter Research Role Signal Pathway Signal Transduction Skeleton Specific qualifier value System Systems Biology Technology Testing Therapeutic Tooth structure Training blastomere structure body system bone bone morphogenetic protein receptors career cell type chromatin immunoprecipitation comparison control craniofacial craniofacial development craniofacial disorder craniofacial structure embryo cell epithelial to mesenchymal transition experience experimental study extracellular gastrulation in silico in vivo in vivo Model loss of function mathematical model morphogens neural neural plate novel prevent programs public health relevance receptor expression response spatiotemporal timeline tool transcriptome sequencing translational approach

项目摘要

PROJECT SUMMARY The cranial neural crest (NC) contributes to the formation of many craniofacial structures including the bones and cartilage of the face, tooth dentin and peripheral ganglia. Cell signaling regulates different aspects of cranial NC specification, epithelial-to-mesenchymal transition (EMT) and differentiation and disruptions in this developmental program results in many cranial NC-derived craniofacial birth defects including craniosynestosis, Treacher Collins and CHARGE syndromes, and cleft palate. BMP signaling plays a crucial role during the specification and differentiation of cranial NC, and more recently, BMP signaling was shown to control cranial NC EMT. A mechanistic understanding of the role of BMP signaling during cranial NC development is essential to develop novel preventative and therapeutic measures against craniofacial defects. This proposal will determine the molecular mechanism of BMP gradient formation in the chick gastrula, and how this gradient regulates the formation of cranial cell types including neural, cranial NC, placode and epidermal fates. These experiments will use in vivo and in silico approaches to test the hypothesis that extracellular BMP ligands are produced primarily by the cranial NC and are actively shuttled over long distances to signal most strongly in the nonneural ectoderm. Next, quantitative expression analysis and live imaging will be used to establish the timeline of BMP signaling during gastrulation and neurulation, and analysis of the resulting datasets will determine population- and single-cell-level responses to BMP signals. Differences in signal timing and strength will then be correlated with direct input into different target genes. Finally, the role of BMP target genes Id1/2/3/4 and Fibin during cranial NC EMT will be investigated using in vivo functional analyses. Together, the results of these aims will provide a comprehensive understanding of the regulation and roles of BMP signaling events during early cranial NC development. In addition to identifying targets for translational avenues to prevent craniofacial birth defects, the mentored phase of this proposal will provide Dr. Michael Piacentino with necessary training as he prepares to begin his independent career. Dr. Marianne Bronner's lab at California Institute of Technology, and his assembled advisory council, provide the necessary tools, expertise, and training environment to efficiently execute the proposed aims and establish Dr. Piacentino's independence. This training will be instrumental as Dr. Piacentino begins his independent research program and will provide the experience needed to make lasting impacts on the field of BMP signaling during craniofacial development.

项目概要颅神经嵴 (NC) 有助于许多颅面结构的形成，包括面部骨骼和软骨、牙齿牙本质和周围神经节。细胞信号传导调节不同方面颅内 NC 规范、上皮间质转化 (EMT) 以及分化和破坏该发育计划导致许多颅脑 NC 衍生的颅面出生缺陷，包括颅缝狭窄、Treacher Collins 和 CHARGE 综合征以及腭裂。 BMP信号传导起着至关重要的作用 BMP 信号在颅脑 NC 的规范和分化过程中发挥着重要作用，最近，BMP 信号传导被证明控制颅脑 NC EMT。从机制上理解 BMP 信号在颅脑 NC 过程中的作用开发针对颅面部疾病的新型预防和治疗措施至关重要缺陷。该提案将确定雏鸡中 BMP 梯度形成的分子机制原肠胚，以及这种梯度如何调节颅细胞类型的形成，包括神经细胞、颅脑 NC、基板和表皮的命运。这些实验将使用体内和计算机方法来测试假设细胞外 BMP 配体主要由颅脑 NC 产生并主动穿梭长距离在非神经外胚层中发出最强烈的信号。接下来，定量表达分析实时成像将用于建立原肠胚形成和神经形成过程中 BMP 信号传导的时间线，对所得数据集的分析将确定群体和单细胞水平对 BMP 的反应信号。信号时序和强度的差异将与不同目标的直接输入相关联基因。最后，将研究BMP靶基因Id1/2/3/4和Fibin在颅NC EMT过程中的作用使用体内功能分析。这些目标的结果将共同提供全面的了解早期颅脑 NC 发育过程中 BMP 信号事件的调节和作用。除了确定预防颅面出生缺陷的转化途径目标外，该提案的指导阶段将为 Michael Piacentino 博士提供必要的培训，帮助他准备开始他的独立生涯。玛丽安·布朗纳 (Marianne Bronner) 博士在加州理工学院的实验室及其组建咨询委员会，提供必要的工具、专业知识和培训环境，以有效地执行拟议的目标并确立皮亚琴蒂诺博士的独立性。该培训将有助于 Piacentino 博士开始了他的独立研究计划，并将提供制作所需的经验。对颅面发育过程中 BMP 信号传导领域产生持久影响。