Cellular Basis of Incisor Asymmetry

门牙不对称的细胞基础

• 批准号: 10707930
• 负责人: Ameera Samaher Haque
• 金额: $ 5.35万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707930
• 关键词: 3-Dimensional; Affect; Apoptosis; Architecture; Atlases; Automobile Driving; Behavior; Biological Process; Bone Resorption; Cell Communication; Cell Proliferation; Cell Shape; Cell Size; Cell division; Cells; Cellular Morphology; Computer software; Cues; Dental; Dental Enamel; Dental Schools; Dentists; Dentition; Dentures; Development; Developmental Biology; Disease; Distal; Embryo; Embryonic Development; Environment; Epithelium; Event; Fellowship; Foundations; Future; Genetic; Goals; Growth; Image; Implant; Incisor; Individual; Intercalated Cell; Investigation; Journals; Knowledge; Mandible; Maps; Measurement; Measures; Mechanics; Mediating; Mentorship; Mesenchymal; Mesenchyme; Modeling; Molecular; Morphogenesis; Morphology; Mus; Natural regeneration; Neck; Nuclear; Organ; Organism; Organogenesis; Osseointegration; Pathway interactions; Positioning Attribute; Process; Proliferating; Qualifying; Research; Resolution; Role; Rotation; SHH gene; Scientist; Series; Shapes; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Specimen; Stratification; Structure; System; Techniques; Testing; Tissues; Tooth Germ; Tooth regeneration; Tooth structure; Training; Work; age effect; career; cell behavior; cell motility; clinical training; comparison control; cyclopamine; design; digital; driving behavior; experimental study; high resolution imaging; improved; in vivo; insight; meetings; migration; morphogens; mutant; novel; pharmacologic; programs; regenerative; regenerative approach; regenerative therapy; restorative dentistry; small molecule inhibitor; software development; spatiotemporal; tissue regeneration

Project Summary Morphogenesis is the biological process by which cells, tissues, and organs acquire the shape that is critical to their function during embryonic development, and it can be repurposed during regeneration of tissues after damage in a mature organism. Work on embryonic explants has revealed that differences in cellular morphologies and mechanical cell-cell interactions, both controlled by signaling molecules, likely drive tissue- specific shapes in multiple epithelial tissues including the symmetric murine molar. Nevertheless, a deeper understanding of the basic principles and cellular behaviors that regulate morphogenesis is required to leverage these processes for future regenerative therapies that can mitigate the effects of aging and disease. I will use the early developmental stages of the murine incisor to study how cell behaviors drive directional growth and morphogenesis. Murine incisor development is highly asymmetric, and the mechanisms regulating this process have remained elusive. Prior studies have shown that perturbations in Sonic Hedgehog (Shh) signaling result in abnormal incisor morphology, and that Shh-dependent cell movement drives tooth bud invagination in the symmetrical molar. Through this proposal, I will test the hypothesis that modulation of the Shh signaling cascade drives changes in cellular morphology and behavior that determine the asymmetric morphogenic development of the incisor. I will measure and quantify localized cellular and tissue morphological changes such as cell shape, nuclear position, and tooth curvature, as well as dynamic cell behaviors such as differential proliferation, oriented cell division, and cell intercalation, using high resolution live imaging and our novel software program, MARGARITA. This will establish a foundational atlas of cell morphologies and behaviors responsible for the epithelial bending events driving early development of the asymmetric incisor (Aim 1). Next, pharmacological perturbation of Shh signaling in incisor explants and spatiotemporal modulation of Shh expression in genetic mutants will determine to what extent the modulation of this signal transduction pathway affects cellular morphology during incisor development (Aim 2). These findings will provide significant insights into basic tooth and developmental biology, which have the potential to be applied towards future dental regenerative therapies. Current strategies to restore missing dentition (i.e., implants, dentures) can lead to significant bone resorption or may fail due to limited osseointegration. Thus, biologically regenerating teeth using morphogenesis-driven techniques has the potential to significantly improve restorative dentistry. These research goals will be conducted in conjunction with a comprehensive training plan designed to develop my career as a dentist-scientist. Training includes structured mentorship from two highly qualified sponsors, as well as scientific and technical training through meetings, seminars, journal clubs, and classes at UCSF, which offers both an outstanding research environment and an excellent dental school for clinical training.

项目摘要 形态发生是细胞、组织和器官获得对 它们在胚胎发育过程中的功能，并可以在组织再生过程中重新使用 对成熟生物体的损害。对胚胎外植体的研究表明，细胞内的差异 形态和细胞-细胞间的机械相互作用都由信号分子控制，可能会驱动组织- 多种上皮组织中的特殊形状，包括对称的小鼠磨牙。尽管如此，更深层次的 需要了解调控形态发生的基本原理和细胞行为 这些过程可用于未来的再生疗法，以减轻衰老和疾病的影响。 我将使用小鼠门牙的早期发育阶段来研究细胞行为如何驱动定向生长 和形态发生。小鼠门牙的发育是高度不对称的，调节这一过程的机制 这一过程仍然难以捉摸。先前的研究表明，Sonic Hedgehog(Shh)信号中的扰动 导致切牙形态异常，依赖Shh的细胞运动驱动牙芽内陷 对称的磨牙。通过这一提议，我将检验Shh信号调制的假设 级联驱动细胞形态和行为的变化，从而决定了不对称的形态发生 门牙的发展。我将测量和量化局部的细胞和组织形态变化，如 如细胞形状、核位置和齿曲率，以及动态细胞行为，如差分 增殖、定向细胞分裂和细胞嵌入，使用高分辨率实时成像和我们的新技术 软件程序，玛格丽塔。这将建立细胞形态和行为的基础图谱 负责推动非对称切牙早期发育的上皮弯曲事件(目标1)。下一首, 切牙组织中Shh信号的药理扰动及Shh的时空调控 在基因突变体中的表达将决定这一信号转导途径的调节程度 在门牙发育过程中影响细胞形态(目标2)。这些发现将提供重要的见解 基础牙齿和发育生物学，它们有可能应用于未来的牙科 再生疗法。目前修复缺失牙列的策略(如种植体、假牙)可能导致 严重的骨吸收或可能由于有限的骨结合而失败。因此，使用生物再生牙齿 形态发生驱动技术有可能显著改善修复牙科。 这些研究目标将与一项全面的培训计划一起进行，旨在制定 我作为牙医科学家的职业生涯。培训包括来自两个高资质赞助商的结构化指导，如 以及通过会议、研讨会、期刊俱乐部和加州大学旧金山分校的课程进行科学和技术培训，这 为临床培训提供卓越的研究环境和优秀的牙科学校。