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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.

项目总结