Genetic, Tissue, and Anatomical Interactions in Mandibulofacial Dysmorphogenesis

下颌面部畸形发生中的遗传、组织和解剖学相互作用

• 批准号: 10663868
• 负责人: Ethylin Wang Jabs
• 金额: $ 73.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663868
• 关键词: 22q11.2; 3-Dimensional; Acids; Affect; Alleles; Anatomy; Apoptosis; Candidate Disease Gene; Cartilage; Cell physiology; Cells; Cleft Palate; Complex; Congenital Abnormality; Crowding; Data; Databases; Development; Developmental Process; Diagnosis; Disease; Dissection; Dysmorphology; Embryo; Emotional; Etiology; Event; Face; Family; Floor; Frequencies; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Histologic; Human; Image; Immunohistochemistry; In Situ Hybridization; Incidence; Individual; Informatics; International; Investigation; Jaw; Knock-out; Knockout Mice; Label; Length; Mandible; Mandibulofacial Dysostosis; Manuals; Methods; Micrognathism; Modeling; Molecular; Morphogenesis; Morphology; Mus; Muscle; Mutant Strains Mice; Mutation; Obstruction; Online Mendelian Inheritance In Man; Operative Surgical Procedures; Palate; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Perinatal mortality demographics; Phenotype; Pierre Robin Syndrome; Process; Production; Proliferating; Protocols documentation; PubMed; Reporting; Robin bird; Severities; Signal Pathway; Signal Transduction; Site; Syndrome; Systems Biology; Testing; Time; Tissue Differentiation; Tissue-Specific Gene Expression; Tissues; Tongue; United States National Institutes of Health; Visualization; base; bone; campomelic dysplasia; craniofacial; craniofacial development; design; embryo tissue; follow-up; genetic variant; histological studies; human data; innovation; laser capture microdissection; microCT; mouse genome; mouse model; mutant; novel; palatal shelves; prenatal; programs; respiratory; response; skull base; therapeutic development; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Anomalies of the face invariably require some type of therapy, corrective surgery, and close follow-up while imposing a financial and emotional burden on patients and their families. Although the analysis of human data is critical, human studies pose particular problems, not the least of which is that critical times of prenatal development are not available for study. This proposal aims to identify the developmental and molecular processes underlying mandibulofacial anomalies using mouse mutants that we identified by systematically searching the current contents of the International Mouse Phenotyping Consortium (IMPC) in response to NIH PAR-20-137 for phenotyping IMPC embryonic and perinatal lethal KO mouse lines. Micro- or retrognathia are the most common terms used to describe mandibular phenotypes in mandibulofacial dysostosis, yet the current lack of precision in diagnoses of mandibular dysmorphology does not critically consider the potentially distinct etiology of these conditions and their influence on potential sequelae of anomalies. Micrognathia describes a mandible that is absolutely reduced in size, indicating that the mandible is primarily affected, while retrognathia refers to a normally sized mandible that is placed posteriorly relative to the upper jaw. Thus, micrognathia and retrognathia, while providing similar facial profiles, are produced by different primary developmental processes and each may integrate differently with tongue and palatal development. When mandibular dysmorphology occurs with glossoptosis, respiratory obstruction, and in some cases, a cleft palate, the condition is referred to as Pierre Robin (PR). A causative pathogenesis of a sequence of developmental events has been hypothesized for PR, but few clear causal relationships between discovered mutations, dysregulated gene expression, precise cellular processes, and PR-associated anomalies are documented. To test this hypothesis, we plan a carefully coordinated and fully collaborative set of analyses of IMPC mutant mouse lines identified based on genes known to be causative for PR in humans or on the presence of PR features recorded in these mouse lines. Our in-depth phenotyping will involve: Aim 1: quantitative 3D morphologic analyses of embryos using phosphotungstic acid-enhanced micro computed tomography; Aim2: differential gene expression analysis of relevant tissues and developmental time points between mutant and unaffected littermate controls using bulk RNA-seq and spatial transcriptomics; Aim 3: histologic studies using in situ hybridization or immunohistochemistry of relevant genes, signaling pathways, cellular processes, and differentiation states to determine the cellular and molecular events giving rise to dysmorphogenesis of the mandibulofacial complex. This multi-level, systems biology approach will provide precise definitions of the localized effects of genetic variants on mandibular and associated tongue, palatal, and upper airway phenotypes to identify the developmental and molecular functions involved in their production, using mouse lines that model the phenotypes associated with these conditions.

项目概要 面部异常总是需要某种类型的治疗、矫正手术和密切随访，同时 给患者及其家人带来经济和情感负担。尽管对人类数据的分析 至关重要的是，人类研究提出了特殊的问题，其中最重要的是产前的关键时期 发展不可供研究。该提案旨在确定发育和分子水平 使用我们系统鉴定的小鼠突变体处理潜在的下颌面部异常 搜索国际小鼠表型联盟 (IMPC) 的当前内容作为回应 NIH PAR-20-137 用于 IMPC 胚胎和围产期致死 KO 小鼠系的表型分析。微或 下颌后缩是描述下颌面骨发育不全中下颌表型的最常用术语， 然而，目前下颌畸形诊断缺乏精确性，并没有严格考虑 这些情况的潜在不同病因及其对异常潜在后遗症的影响。 小颌畸形是指下颌骨的尺寸绝对减小，表明下颌骨主要是 受影响，而下颌后缩是指正常大小的下颌骨相对于上颌骨位于后方 颚。因此，小颌畸形和下颌后缩虽然具有相似的面部轮廓，但却是由不同的原发性细胞产生的。 发育过程，每个过程都可能与舌头和上颚发育有不同的整合。什么时候 下颌畸形伴有舌下垂、呼吸阻塞，在某些情况下还伴有腭裂， 这种情况被称为 Pierre Robin (PR)。一系列发育的致病机制 事件已被假设为 PR，但发现的突变之间很少有明确的因果关系， 基因表达失调、精确的细胞过程以及与 PR 相关的异常都被记录下来。到 检验这个假设，我们计划了一套精心协调和充分协作的 IMPC 突变小鼠分析 根据已知导致人类 PR 的基因或 PR 特征的存在而鉴定的品系 记录在这些小鼠线中。我们深入的表型分析将涉及： 目标 1：定量 3D 形态学 使用磷钨酸增强显微计算机断层扫描对胚胎进行分析；目标2：差异化 相关组织的基因表达分析以及突变体和未受影响之间的发育时间点 使用批量 RNA 测序和空间转录组学进行同窝对照；目标 3：使用原位进行组织学研究 相关基因、信号通路、细胞过程和的杂交或免疫组织化学 分化状态以确定引起形态发生异常的细胞和分子事件 下颌面部复合体。这种多层次的系统生物学方法将提供精确的定义 遗传变异对下颌及相关舌、腭和上呼吸道表型的局部影响 使用模拟小鼠品系来识别其生产中涉及的发育和分子功能 与这些条件相关的表型。