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 为了为颅面畸形，疾病和伤害设计新的创新治疗方法，更多的研究是 需要了解控制适当下颌形成的发育机制。正常面部 形态发生涉及胚胎大脑与面部之间的准确时机相互作用。独立面部 Primordia生长，直到它们插入并融合形成功能性下颌。由于此过程的复杂性，它是 毫不奇怪的是，下巴异常，包括与尺寸相关的下巴不规则性，例如微处理，retrognathia， 最常见的先天缺陷之一，上颌下降，口感和唇裂是最常见的。这项研究会 通过关注大脑和/或面对面的改变，提供关键数据来满足这种未满足的需求 在早期发展期间，影响面部原始融合的时间和成功。我们采用独特的嵌合体 操纵任何一种神经rest间充质的系统，这是引起大多数的细胞种群 颅面骨骼或基础前脑。小鸡和鸭的下巴和成熟速率非常不同 因此，在鸭和小鸡胚胎之间移植神经褶皱或基础前脑会产生嵌合体 携带两个通过物种特异性细胞和分子机制的区别细胞群 形状和大小的差异将实现。 先前关于唇裂病因的研究确定面部突出增长的失调发挥了作用 一个主要角色，因为关键的发展事件（例如面部突出接触和融合）取决于 关于成功的增长。此外，我们来自胚胎面部发育形态的数据 形态发生预测，大脑生长会影响表型的形状和时空特征 发生这些关键事件的景观。这些结果表明，不仅有分子 面部和大脑之间起着关键作用的相互作用，但也有建筑组成部分 对于成功的面部突出融合至关重要的大脑。 该应用程序旨在通过实验测试以下假设。 早期发育过程中的大脑和/或面部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，这有助于增加c裂的责任。目标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 和凋亡）在融合后胚胎中。 AIM 2将确定对Wnt-的改变的程度 信号传导会影响融合的成功并改变裂纹的责任。这个目标将提供特定的见识 变成Wnt信号的分子机制，可以传播跨物种的颅面形状变化。 总之，这两个目标将极大地增加我们对大脑和面对面的贡献的理解。