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.

项目总结 为了设计新的颅面畸形、疾病和损伤的创新治疗方法，更多的研究正在进行 需要了解控制适当的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，直到它们对生并融合形成有功能的颌骨。由于这个过程的复杂性，它是 不足为奇的是，颌骨异常，包括与大小有关的颌骨异常，如小颌下垂，下颌后缩， 而上颌发育不全、腭裂和唇裂是最常见的出生缺陷。这项研究将 提供关键数据，通过关注如何改变大脑和/或脸部的生长来满足这一未得到满足的需求 发育早期影响面神经原基融合的时间和成功与否。我们雇佣了一个独一无二的嵌合体 系统来操纵神经脊间充质，这是产生大多数 颅面骨，或称基底前脑。小鸡和鸭子的下巴和成熟率是非常不同的 因此，在鸭和鸡胚胎之间移植神经折叠或基底前脑会产生嵌合体， 携带两个独特的细胞群体，具有物种特有的细胞和分子机制 在形状和大小上实现了哪些差异。 以前对唇裂病因的研究已经确定面部隆起生长的失调在其中起作用。 一个重要的角色，因为面部隆起接触和融合等关键发育事件是相互依存的 关于成功的成长。此外，我们的数据来自胚胎面部的发育形态 形态发生学预测脑生长影响表型的形状和时空特征 这些关键事件发生的环境。这些结果表明，不仅存在分子上的 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 大脑对成功的面部隆起融合至关重要。 这项应用的目的是从实验上检验这样一种假设，即调节生长的大小和/或时机 大脑和/或面部在早期发育过程中的畸形会增加唇裂的发生率。此外，这项研究将 确定早期胚胎中最小的区域/组织，这些区域/组织有助于增加分裂的风险。目标1 将测试大小和时空生长的变化如何影响脸型和细胞过程(增殖 和细胞凋亡)在融合前后的胚胎中。目标2将确定对WNT的更改程度- 信号传递影响融合的成功，并改变裂隙的易感性。这一目标将提供具体的见解 WNT信号在不同物种之间传播颅面形状差异的分子机制。 这两个目标结合在一起，将大大增加我们对大脑和面部对唇裂的贡献的理解。