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.

项目概要 为了设计针对颅面畸形、疾病和损伤的创新疗法，需要进行更多研究 需要了解控制正确下颌形成的发育机制。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 原基生长直至并列并融合形成功能性颌骨。由于这个过程的复杂性， 毫不奇怪，下颌异常，包括与大小相关的下颌不规则，例如小下颌、下颌后缩、 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 通过关注如何改变大脑和/或面部的生长来提供关键数据来解决这一未满足的需求 在早期发育过程中影响面部原基融合的时间和成功。我们采用独特的嵌合体 操纵神经嵴间充质的系统，神经嵴间充质是产生大多数神经嵴的细胞群 颅面骨，或基底前脑。小鸡和鸭子的下巴和成熟速度都非常不同 因此，在鸭和鸡胚胎之间移植神经褶皱或基底前脑会产生嵌合体 携带两种独特的细胞群，它们具有物种特异性的细胞和分子机制 实现了形状和尺寸的差异。 先前对唇裂病因学的研究已确定，面部突出生长失调起着重要作用 起着重要作用，因为面部突出接触和融合等关键发育事件是依赖的 关于成功的成长。此外，我们来自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 这些关键事件发生的景观。这些结果表明，不仅存在分子 面部和大脑之间的相互作用发挥着关键作用，但也存在结构组成部分 大脑对于面部突出融合的成功至关重要。 该应用旨在通过实验检验以下假设：调节生长的大小和/或时间 早期发育期间大脑和/或面部的损伤会增加唇裂的发生率。此外，本研究将 确定早期胚胎中有助于增加分裂可能性的最小区域/组织。目标1 将测试尺寸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）在融合前至融合后的胚胎中。目标 2 将确定 WNT- 的改变程度 信号传导影响融合的成功并改变分裂的可能性。这个目标将提供具体的见解 深入研究 WNT 信号传递跨物种颅面形状变异的分子机制。 这两个目标共同将大大加深我们对大脑和面部对裂缝的贡献的理解。