The regulation and cellular dynamics of neural crest cell delamination in mammalian craniofacial development

哺乳动物颅面发育中神经嵴细胞分层的调控和细胞动力学

• 批准号: 10634594
• 负责人: Emma Moore
• 金额: $ 3.25万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634594
• 关键词: Actins; Address; Affect; Automobile Driving; Basal Cell; Biophysical Process; Birds; Budgets; Cells; Cephalic; Chemicals; Congenital Abnormality; Craniofacial Abnormalities; Crowding; Cytoskeletal Proteins; Cytoskeleton; Data; Development; Disease; Embryo; Embryonic Development; Environment; Epithelium; Etiology; Evolution; Generations; Genes; Genetic; Healthcare; Heterozygote; Human; Individual; Ion Channel; Knock-out; Knowledge; Mammals; Measures; Mediating; Mesenchymal; Microtubules; Molecular; Morphology; Mus; Mutation; Neural Crest Cell; Neuroepithelial Cells; Nonmuscle Myosin Type IIA; Operative Surgical Procedures; Pathogenesis; Phase; Piezo 1 ion channel; Play; Population; Prevention; Preventive therapy; Process; Prognosis; Regulation; Research; Research Proposals; Role; Signal Pathway; Skeleton; Specific qualifier value; Stretching; System; Testing; Tissues; Visualization; body system; craniofacial; craniofacial development; craniofacial disorder; craniofacial tissue; gain of function; gene regulatory network; improved; inhibitor; innovation; loss of function; migration; neuroepithelium; neuroimaging; novel; single-cell RNA sequencing; spatiotemporal; stem; stem cells; therapy development; transcription factor; transcriptomics

Project Summary Craniofacial anomalies account for a third of all human congenital birth defects and significantly impact national health care budgets. Affected individuals typically undergo multiple surgeries throughout their lifetime, which are rarely fully corrective. Therefore, it is critical to develop therapies for improved prognosis and prevention, but this can only come from a better understanding of the genetic and cellular mechanisms governing craniofacial development and the etiology and pathogenesis of individual disorders. Disruptions in neural crest cell (NCC) development are considered the underlying cause of many craniofacial birth defects. Therefore, understanding the genetic and cellular mechanisms that regulate NCC development and their ultimate generation of craniofacial tissue is crucial for developing preventative therapies and improved surgical prognosis. Delamination from the neuroepithelium is a critical step in the formation of migrating NCC. However, the molecular and cellular mechanisms governing NCC delamination in mammalian embryos are poorly understood. Delamination is a biophysical process by which a cell departs its tissue environment, and my extensive preliminary data indicates that cell extrusion may be a novel mechanism facilitating cranial NCC delamination. This proposal focuses on cell extrusion and will broaden our understanding of NCC delamination by elucidating the cellular and genetic systems regulating NCC delamination via cell extrusion. Aim1 will visualize and capture the dynamic cytoarchitectural and morphological changes that drive cranial NCC delamination in mouse embryos. Aim2 will investigate the role of Piezo1, a mechanosensitive ion channel in cranial NCC delamination and craniofacial development. The impact of Piezo1 loss-of-function on NCC delamination and craniofacial development will be analyzed through null and conditional genetic knock out of Piezo1 mechanosensitive ion channels in mouse embryos. The downstream regulatory network and signaling pathways will then be elucidated through transcriptomic comparisons measuring the differences in candidate downstream regulators between wild type and knock out embryos. Completion of the study will advance fundamental knowledge and further our understanding of neural crest cell and craniofacial development and of congenital birth defects.

项目摘要 颅面异常占所有人类先天性先天缺陷的三分之一，并显着影响 国家卫生保健预算。受影响的个体通常会在一生中接受多次手术， 很少完全纠正。因此，开发疗法以改善预后和 预防，但这只能来自对遗传和细胞机制的更好理解 管理颅面发育以及个体疾病的病因和发病机理。中断 神经rest细胞（NCC）发育被认为是许多颅面先天缺陷的根本原因。 因此，了解调节NCC发育及其它们的遗传和细胞机制 颅面组织的最终产生对于开发预防疗法和改善手术至关重要 预后。 神经上皮的分层是迁移NCC形成的关键步骤。然而， 哺乳动物胚胎中管理NCC分层的分子和细胞机制较差 理解。分层是一个生物物理过程，细胞通过其离开组织环境，而我 广泛的初步数据表明，细胞挤出可能是促进颅NCC的新机制 分层。该提案的重点是细胞挤出，将扩大我们对NCC分层的理解 通过阐明通过细胞挤出调节NCC分层的细胞和遗传系统。 AIM1将 可视化和捕获动态的细胞结构和形态学变化，这些变化驱动颅内NCC 小鼠胚胎中的分层。 AIM2将研究Piezo1的作用，Piezo1是机械敏感的离子通道 颅内NCC分层和颅面发展。压电1功能丧失对NCC的影响 分层和颅面发育将通过无效和有条件的遗传敲除 小鼠胚胎中的压电1机械敏感离子通道。下游监管网络和信号传导 然后，将通过转录组比较来阐明途径，以测量候选者的差异 野生型和淘汰胚胎之间的下游调节器。研究的完成将进步 基本知识以及我们对神经rest细胞和颅面发展的理解以及 先天性先天缺陷。