Cartilage and bone of the lower jaw in development and disease

下颌软骨和骨骼的发育和疾病

• 批准号: 10552606
• 负责人: Ethylin Wang Jabs
• 金额: $ 76.69万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552606
• 关键词: 3-Dimensional; Acids; Affect; Anatomy; Anterior; Area; Atlases; Automobile Driving; Behavior; C57BL/6 Mouse; Cartilage; Cell Lineage; Cell Proliferation; Cells; Chondrocytes; Complex; Congenital Abnormality; Coupled; Data; Defect; Dermal; Development; Disease; Embryo; Embryonic Development; Emotional; Event; Evolution; Family; First Pharyngeal Arch; Genes; Growth; Histologic; Human; Hypertrophy; Image; Incus; Individual; Investigation; Jaw; Knowledge; Length; Ligaments; Link; Location; LoxP-flanked allele; Malleus; Mammals; Mandible; Mandibular Diseases; Meckel' s cartilage; Methods; Micrognathism; Modeling; Modernization; Molecular; Morphogenesis; Mus; Natural regeneration; Neural Crest Cell; Newborn Infant; Operative Surgical Procedures; Pathway Analysis; Patients; Pharyngeal structure; Phenotype; Phylogenetic Analysis; Physiologic Ossification; Population; Positioning Attribute; Prevention; Process; Quality of life; Reporter; Research; Respiration; Rod; Role; Sampling; Shapes; Skeleton; Source; Speech; Stains; Structure; Syndrome; Tamoxifen; Three-Dimensional Imaging; Time; Tissue-Specific Gene Expression; Tissues; Tubular formation; Variant; Vertebrates; airway obstruction; base; biological research; bone; bone repair; cartilage cell; cartilage development; cartilaginous; craniofacial; design; experimental study; feeding; innovation; microCT; middle ear; migration; mineralization; mutant; novel; novel strategies; scaffold; spatiotemporal; success; therapeutic development; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY The lower jaw evolved as a structure composed of many bones the largest of which, the dentary, persists as a single lower jawbone in modern mammals, and is referred to as the mandible in humans. Mandibular disorders, often resulting in small jaws, are among the most common human birth defects. These disorders can dramatically affect quality of life, and are often associated, or compound problems with airway obstruction, speech, and feeding. During embryogenesis, development of the mandible is preceded by and associated with a tubular cartilage rod called Meckel's cartilage (MC) and anomalies of MC have been associated with mandibular disorders. Development of MC in modern mammals is complex: the anterior part contributes to the formation of the mandibular symphysis, its posterior part forms cartilages that mineralize endochondrally to form two middle ear bones, and the posterior half of the middle region forms ligaments. Less is known about the anterior half of the middle region of MC, which is transient, present during a small window of embryonic development before it disappears. Established assessments describe MC as a template for the formation of the mandible, but evidence of this is lacking and little is known of the relationship between the midportion of MC and mandibular mineralization, size, and shape or the processes of MC growth in length, perichondrial ossification, and disappearance of MC. We present data demonstrating that MC does not serve as a template in the way cartilaginous models function in endochondral ossification and hypothesize a new role for the mid portion of MC in determining mandibular length, mineralization of the perichondrium, mineralization of the mandible, and its disappearance. Because our findings challenge the traditional role of MC, we have designed this project to validate the developmental events that take place as the midportion of MC disappears and the mandible forms through a detailed analysis of four processes: 1) initiation and growth in length of MC; 2) mineralization of MC perichondrium; 3) mineralization of the mandible; and 4) disappearance of MC. Our approach is based on knowledge we have gained through preliminary investigations of these processes occurring at different times along the length of MC, and spanning the buccal to lingual aspects of the interior of MC. We couple 3D imaging with tissue and cellular analyses of embryonic mutant Sox9flox/flox;Col2a1-CreERT, and Sox9flox/flox mice to precisely define the changing cellular dynamics of the lower jaw in developmental time and anatomical space. These data are used in turn to inform our RNA-seq analyses of the developing MC and mandible directed at recovering the underlying transcriptome by differential gene expression, pathway, and network analyses. We plan cell lineage tracing experiments to determine the fate of cells from the intermediate region of MC, those that initiate MC perichondrial mineralization, and mandible mineralization. Our integrative approach is designed to bring new understanding to lower jaw development and open novel research areas to advance strategies for bone repair, regeneration, and prevention in mandibular disease.

项目概要 下颌进化为由许多骨头组成的结构，其中最大的牙骨一直作为 现代哺乳动物中的单个下颌骨，在人类中被称为下颌骨。下颌疾病， 通常导致下颌较小，是最常见的人类出生缺陷之一。这些疾病可以显着 影响生活质量，并且通常与气道阻塞、言语和呼吸困难相关或复杂。 喂养。在胚胎发生过程中，下颌骨的发育先于管状结构并与之相关。 称为梅克尔软骨 (MC) 的软骨棒，MC 的异常与下颌骨相关 失调。现代哺乳动物中 MC 的发育是复杂的：前部有助于形成 下颌联合，其后部形成软骨，软骨内矿化形成两个中间 耳骨，中间区域的后半部分形成韧带。关于前半部分知之甚少 MC 的中间区域是短暂的，存在于其之前的胚胎发育的一个小窗口期 消失。已建立的评估将 MC 描述为下颌骨形成的模板，但证据 对此缺乏了解，并且对于 MC 中部和下颌骨之间的关系知之甚少 矿化、大小和形状或 MC 长度生长过程、软骨膜骨化和 MC的消失。我们提供的数据证明 MC 不能作为模板 软骨模型在软骨内骨化中发挥作用并假设 MC 中部的新作用 确定下颌长度、软骨膜矿化、下颌骨矿化及其 消失。因为我们的发现挑战了 MC 的传统角色，所以我们设计这个项目是为了 验证 MC 中部消失时发生的发育事件和下颌骨形状 通过对四个过程的详细分析：1）MC的起始和长度的增长； 2）MC的矿化 软骨膜； 3）下颌骨矿化； 4）MC消失。我们的方法基于 我们通过对不同时间发生的这些过程的初步调查获得的知识 沿着 MC 的长度，并跨越 MC 内部的颊侧到舌侧。我们结合 3D 成像 对胚胎突变体 Sox9flox/flox;Col2a1-CreERT 和 Sox9flox/flox 小鼠进行组织和细胞分析 精确定义下颌在发育时间和解剖空间中变化的细胞动力学。 这些数据依次用于为我们针对发育中的 MC 和下颌骨进行 RNA 测序分析 通过差异基因表达、通路和网络分析恢复潜在的转录组。我们 计划细胞谱系追踪实验以确定来自 MC 中间区域的细胞的命运，这些细胞 启动 MC 软骨膜矿化和下颌骨矿化。我们的综合方法旨在 为下颌发育带来新的认识，并开辟新的研究领域，以推进策略 下颌骨疾病的骨修复、再生和预防。