Integration of Brain and Face Morphogenesis in Normal and Disease Phenotypes

正常和疾病表型中大脑和面部形态发生的整合

• 批准号: 10826915
• 负责人: Zuzana Vavrusova
• 金额: $ 7.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10826915
• 关键词: 3-Dimensional; Acceleration; Address; Adult; Affect; Agonist; Apoptosis; Architecture; Binding; Birds; Brain; Brain region; Cell physiology; Cells; Chick; Chick Embryo; Chickens; Chimera organism; Cleft Lip; Cleft Palate; Complex; Congenital Abnormality; Craniofacial Abnormalities; Data; Development; Disease; Ducks; Electroporation; Embryo; Etiology; Event; Exhibits; Face; Family; Frontonasal Prominence; Gene Expression; Goals; Growth; Histological Techniques; Human; Incidence; Individual; Injury; Jaw; Maxilla; Maxillary Prominence; Mediating; Mesenchyme; Micrognathism; Modeling; Molecular; Morphogenesis; Mouse Strains; Mus; Neural Crest; Neural Fold; Neural Pathways; Palate; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Premaxillary palate; Process; Proliferating; Prosencephalon; Research; Risk; Role; SHH gene; Series; Severities; Shapes; Signal Transduction; Structural defect; Surface Ectoderm; System; Testing; Time; Tissues; Transplantation; Variant; WNT Signaling Pathway; Work; antagonist; basal forebrain; beta catenin; brain size; cleft lip and palate; craniofacial; craniofacial bone; craniofacial development; disease phenotype; genetic approach; in silico; innovation; insight; internal control; lip morphogenesis; malformation; member; microCT; mouse model; predictive modeling; success

PROJECT SUMMARY To devise new innovative treatments for craniofacial malformations, disease, and injuries, more research is needed to understand developmental mechanisms that control proper jaw formation. Normal facial morphogenesis involves precisely timed interactions between the embryonic brain and face. Independent facial primordia grow until they appose and fuse to form functional jaws. Due to the complexity of this process, it is unsurprising that the jaw anomalies, including size-related jaw irregularities such as micrognathia, retrognathia, and maxillary hypoplasia, cleft palate, and cleft lip are among the most common birth defects. This study will provide critical data to address this unmet need by focusing on how altering growth of the brain and/or face during early development influence the time and success of facial primordia fusion. We employ a unique chimeric system to manipulate either neural crest mesenchyme, which is the cell population that gives rise to most of the craniofacial bones, or basal forebrain. Chick and duck have very different jaws as well as rates of maturation thus, transplanting neural folds or basal forebrain between duck and chick embryos generates chimeras that carries two distinguished cell populations that have species-specific cellular and molecular mechanisms through which differences in shape and size are achieved. Previous research of the etiology of cleft lip has determined that dysregulation of facial prominence growth plays a major role, because key developmental events such as the facial prominence contact and fusion are dependent on successful growth. Additionally, our data from a developmental morphospace of embryonic facial morphogenesis predicts that brain growth impacts the shape and spaciotemporal character of the phenotypic landscape in which these critical events occur. These results indicate that there are not only molecular interactions between the face and brain that play a key role, but also that there are architectural components of the brain that are critical to successful facial prominence fusion. This application aims to experimentally test the hypothesis that modulation of the size and/or timing of the growth of the brain and/or face during early development increases the incidence of cleft lip. Further, this study will determine the smallest regions/tissues in early embryo that contribute to increasing the liability of clefting. Aim 1 will test how variation in size and spaciotemporal growth affect face shape and cellular processes (proliferation and apoptosis) in embryos pre- to post fusion. Aim 2 will determine the extent to which alterations to WNT- signaling affects the success of fusion and changes the liability of clefting. This aim will provide specific insight into molecular mechanisms of WNT-signaling that propagate craniofacial shape variation across species. Together, the two Aims will add significantly to our understanding of the contributions of brain and face to clefting.

项目摘要 为了设计新的创新治疗颅面畸形，疾病和损伤，更多的研究是 需要了解控制正确颌骨形成的发育机制。正常面部 形态发生涉及胚胎大脑和面部之间精确定时的相互作用。独立面部 原基生长直到它们并置并融合形成功能性的颚。由于这一过程的复杂性， 毫不奇怪，颌骨异常，包括大小相关的颌骨不规则，如小颌，缩颌， 上颌骨发育不全，腭裂，唇裂是最常见的出生缺陷。本研究将 提供关键数据，通过关注如何改变大脑和/或面部的生长， 影响面部原基融合的时间和成功。我们使用了一种独特的嵌合体 系统操纵神经嵴间充质，这是细胞群，产生了大部分的 颅面骨或基底前脑鸡和鸭有非常不同的颌骨以及成熟的速度 因此，在鸭和鸡胚胎之间移植神经褶皱或基底前脑产生嵌合体， 携带两种不同的细胞群，具有物种特异性的细胞和分子机制， 实现了形状和尺寸上的差异。 先前的唇裂病因学研究已经确定，面部突起生长失调在唇裂的发病中起着重要作用。 一个主要的角色，因为关键的发展事件，如面部突出接触和融合是依赖于 成功的成长。此外，我们从胚胎面部发育形态空间的数据， 形态发生预测，大脑生长影响表型的形状和时空特征， 这些重大事件发生的地方。这些结果表明，不仅有分子 面部和大脑之间的相互作用起着关键作用，但也有建筑组件， 对成功的面部突出融合至关重要。 本申请旨在实验性地测试生长的大小和/或时间的调节 在早期发育过程中，大脑和/或面部的损伤会增加唇裂的发病率。此外，这项研究将 确定早期胚胎中有助于增加裂缝可能性的最小区域/组织。要求1 将测试大小和时空生长的变化如何影响面部形状和细胞过程（增殖 和细胞凋亡）。目标2将确定对WNT进行更改的程度- 信号传导影响融合的成功并改变裂开的可能性。这一目标将提供具体的见解 WNT信号的分子机制，传播颅面形状的变化跨越物种。 这两个目标将大大增加我们对大脑和面部对分裂的贡献的理解。